記述言語：英語  

Intracranial mesenchymal chondrosarcoma (MCS) is a rare neoplasm. The diagnosis of MCS is confirmed by the presence of a biphasic pattern on histological examination, comprising undifferentiated small round cells admixed with islands of well-differentiated hyaline cartilage; however, a differential diagnosis may be challenging in some cases. A 28-year-old woman with a 2-month history of headache was referred to our hospital. Radiologic studies showed an extra-axial lobulated mass composed of calcified and uncalcified areas occupying the left middle fossa. Surgical resection was planned, but her headache suddenly worsened before her planned hospital admission and she was admitted as an emergency. Radiologic studies showed an acute hemorrhage in the uncalcified part of the mass. The mass was resected via the left zygomatic approach after embolization of the feeder vessels. The most likely histopathological diagnosis was MCS. However, the typical bimorphic pattern was not identified in our surgical samples; each undifferentiated area and well-differentiated area was observed separately in different tissue specimens, and no islands of well-differentiated hyaline cartilage were identified within the undifferentiated areas in the same specimen. Molecular assays confirmed the presence of HEY1-NCOA2 fusion. IRF2BP2-CDX1 fusion and IDH1/2 mutations were negative. The final diagnosis of MCS was made based on the presence of HEY1-NCOA2 gene fusion. MCS should be included in the differential diagnosis when radiologic studies show an extra-axial lobulated mass with calcification. Furthermore, molecular demonstration of HEY1-NCOA2 gene fusion may help make a precise diagnosis of MCS, especially in surgical samples lacking the typical histopathological features.

DOI： 10.2176/nmccrj.cr.2019-0123

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：ELSEVIER SCIENCE INC  

Arginine-glycine-aspartate (RGD)-carrying microbubbles (MBs) have been utilized as a specific contrast agent for glycoprotein IIb/IIIa (alpha(IIb)beta(3) integrin)-expressing activated platelets in ultrasound molecular imaging. Recently, we found that surface modification with lactadherin provides the RGD motif on the surface of phosphatidylserine-containing clinically available MBs, Sonazoid. Here, we examined the potential of lactadherin-bearing Sonazoid MBs to be targeted MBs for glycoprotein IIb/IIIa using the custom-designed in vitro settings with recombinant alpha(IIb)beta(3) integrin, activated platelets or erythrocyte-rich human clots. By modification of the surface with lactadherin, a large number of Sonazoid MBs were attached to the alpha(IIb)beta(3) integrin-coated and platelet-immobilized plate. Additionally, the video intensity of clots after incubation with lactadherin-bearing Sonazoid MBs was significantly higher than that with unmodified Sonazoid MBs, implying the number of attached Sonazoid MBs was increased by the modification with lactadherin. Our results suggest that the lactadherin-bearing Sonazoid MBs have the potential to be thrombus-targeted MBs. (E-mail: otani@ncvc.go.jp) (C) 2019 World Federation for Ultrasound in Medicine & Biology. All rights reserved.

DOI： 10.1016/j.ultrasmedbio.2019.01.022

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：ELSEVIER SCIENCE INC  

The usefulness of ultrasound molecular imaging with alpha(v)beta(3) integrin-targeted microbubbles for detecting tumor angiogenesis has been demonstrated. Recently, we developed alpha(v)beta(3) integrin-targeted microbubbles by modifying clinically available microbubbles (Sonazoid, Daiichi-Sankyo Pharmaceuticals, Tokyo, Japan) with a secreted glycoprotein (lactadherin). The aims of our present study were to simplify the preparation of lactadherin-bearing Sonazoid and to examine the diagnostic utility of lactadherin-bearing Sonazoid for alpha(v)beta(3) integrin-expressing tumor vessels by using SK-OV-3-tumor-bearing mice. By incubating 1.2 x 107 Sonazoid microbubbles with 1.0 mu g lactadherin, the complicated washing and centrifugation steps during the microbubble preparation could be omitted with no significant reduction in labeling ratio of lactadherin-bearing Sonazoid. In addition, the number of Sonazoid microbubbles accumulated in the SK-OV-3 tumor was significantly increased by modifying Sonazoid with lactadherin. Our data suggest that the lactadherin-bearing Sonazoid is an easily prepared and potentially clinically translatable targeted microbubble for alpha(v)beta(3) integrin-expressing vessels. (E-mail: otani@ncvc.go.jp) (c) 2018 World Federation for Ultrasound in Medicine & Biology. All rights reserved.

DOI： 10.1016/j.ultrasmedbio.2018.01.017

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記述言語：英語   出版者・発行元：SPRINGER JAPAN KK  

The recent development of computer technology has made it possible to simulate the hemodynamics of congenital heart diseases on a desktop computer. However, multi-scale modeling of the cardiovascular system based on computed tomographic and magnetic resonance images still requires long simulation times. The lumped parameter model is potentially beneficial for real-time bedside simulation of congenital heart diseases. In this review, we introduce the basics of the lumped parameter model (time-varying elastance chamber model combined with modified Windkessel vasculature model) and illustrate its usage in hemodynamic simulation of congenital heart diseases using examples such as hypoplastic left heart syndrome and Fontan circulation. We also discuss the advantages of the lumped parameter model and the problems for clinical use.

DOI： 10.1007/s12576-017-0585-1

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：AMER PHYSIOLOGICAL SOC  

Although electrical activation of the carotid sinus baroreflex (baroreflex activation therapy) is being explored as a device therapy for resistant hypertension, possible effects on baroreflex dynamic characteristics of interaction between electrical stimulation and pressure inputs are not fully elucidated. To examine whether the electrical stimulation of the baroreceptor afferent nerve impedes normal short-term arterial pressure (AP) regulation mediated by the stimulated nerve, we electrically stimulated the right aortic depressor nerve (ADN) while estimating the baroreflex dynamic characteristics by imposing pressure inputs to the isolated baroreceptor region of the right ADN in nine anesthetized rats. A Gaussian white noise signal with a mean of 120 mmHg and standard deviation of 20 mmHg was used for the pressure perturbation. A tonic ADN stimulation (2 or 5 Hz, 10 V, 0.1-ms pulse width) decreased mean sympathetic nerve activity (367.0 +/- 70.9 vs. 247.3 +/- 47.2 arbitrary units, P < 0.01) and mean AP (98.4 +/- 7.8 vs. 89.2 +/- 4.5 mmHg, P < 0.01) during dynamic pressure perturbation. The ADN stimulation did not affect the slope of dynamic gain in the neural arc transfer function from pressure perturbation to sympathetic nerve activity (16.9 +/- 1.0 vs. 14.7 +/- 1.6 dB/decade, not significant). These results indicate that electrical stimulation of the baroreceptor afferent nerve does not significantly impede the dynamic characteristics of the arterial baroreflex concomitantly mediated by the stimulated nerve. Short-term AP regulation by the arterial baroreflex may be preserved during the baroreflex activation therapy.

DOI： 10.1152/ajpregu.00328.2017

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記述言語：英語   出版者・発行元：LIPPINCOTT WILLIAMS & WILKINS  

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：AMER PHYSIOLOGICAL SOC  

Although the pulsatility of an input pressure is an important factor that determines the arterial baroreflex responses, whether the difference in the input waveforms can meaningfully affect the baroreflex function remains unknown. This study aimed to compare baroreflex responses between two distinct pressure waveforms: a forward saw wave (FSW) and a backward saw wave (BSW). In seven anesthetized rats, carotid sinus pressure was exposed to the FSW or the BSW with a mean of 120 mmHg, pulse pressure of 40 mmHg, and pulse frequency of 1 Hz. Changes in efferent sympathetic nerve activity (SNA) and arterial pressure (AP) during six consecutive saw wave trials (FSW1, BSW1, FSW2, BSW2, FSW3, and BSW3) were examined. The steady-state SNA value during FSW1 was 91.1 +/- 1.9%, which was unchanged during FSW2 and FSW3 but significantly increased during BSW1 (106.6 +/- 3.4%, P < 0.01), BSW2 (110.6 +/- 2.5%, P < 0.01), and BSW3 (111.6 +/- 2.3%, P < 0.01). The steady-state AP value during FSW1 was 98.2 +/- 8.1 mmHg, which was unchanged during FSW2 and FSW3 but significantly increased during BSW1 (106.7 +/- 7.4 mmHg, P < 0.01), BSW2 (105.6 +/- 7.8 mmHg, P < 0.01), and BSW3 (103.8 +/- 7.2 mmHg, P < 0.05). In conclusion, the FSW was more effective than the BSW in reducing mean SNA and AP. The finding could be applied to designing an artificial pulsatile pressure such as that generated by left ventricular assist devices.NEW & NOTEWORTHY This study examined whether the waveforms of an input pressure alone can affect the baroreflex function by using a forward saw wave and a backward saw wave with the same mean pressure, pulse pressure, and pulse frequency. The forward saw wave was more effective than the backward saw wave in reducing sympathetic nerve activity and arterial pressure. The finding could be applied to designing an artificial pulsatile pressure such as that generated by left ventricular assist devices.

DOI： 10.1152/japplphysiol.00354.2017

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：SPRINGER JAPAN KK  

This study examined the mechanism of release of endogenous acetylcholine (ACh) in rabbit renal cortex by applying a microdialysis technique. In anesthetized rabbits, a microdialysis probe was implanted into the renal cortex and perfused with Ringer's solution containing high potassium concentration, high sodium concentration, a Na+/K+-ATPase inhibitor (ouabain), or an epithelial Na+ channel blocker (benzamil). Dialysate samples were collected at baseline and during exposure to each agent, and ACh concentrations in the samples were measured by high-performance liquid chromatography. High potassium had no effect on renal ACh release. High sodium increased dialysate ACh concentrations significantly. Ouabain increased dialysate ACh concentration significantly. Benzamil decreased dialysate ACh concentrations significantly both at baseline and under high sodium. The finding that high potassium-induced depolarization does not increase ACh release suggests that endogenous ACh is released in renal cortex mainly by non-neuronal mechanism. Sodium ion transport may be involved in the non-neuronal ACh release.

DOI： 10.1007/s12576-016-0489-5

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：AMER PHYSIOLOGICAL SOC  

DOI： 10.1152/ajpheart.00315.2017

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：ELSEVIER  

Desipramine (DMI) is a blocker of neuronal norepinephrine (NE) uptake transporter. Although intravenous DMI has been shown to cause centrally-mediated sympathoinhibition and peripheral NE accumulation, its parasym-pathetic effect remains to be elucidated. We hypothesized that intravenous DMI activates the cardiac vagal nerve via an alpha(2)-adrenergic mechanism. Using a cardiac microdialysis technique, changes in myocardial interstitial acetylcholine (ACh) levels in the left ventricular free wall in response to intravenous DMI (1 mg center dot kg(-1)) were examined in anesthetized rats. In rats with intact vagi (n = 7), intravenous DMI increased ACh from 1.67 +/- 0.43 to 2.48 +/- 0.66 nM (P < 0.01). In rats with vagotomy (n = 5), DMI did not significantly change ACh (from 0.92 +/- 0.16 to 0.85 +/- 0.23 nM). In rats with intact vagi pretreated with intravenous yohimbine (2 mg center dot kg(-1)), DMI did not significantly change ACh (from 1.25 +/- 0.23 to 1.13 +/- 0.15 nM). In conclusion, while DMI is generally considered to be an agent that predominantly affects sympathetic neurotransmission, it can activate the cardiac vagal nerve via alpha(2)-adrenergic stimulation in experimental settings in vivo. (C) 2017 Elsevier B.V. All rights reserved.

DOI： 10.1016/j.autneu.2017.02.005

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：AMER PHYSIOLOGICAL SOC  

Recent clinical trials in patients with drug-resistant hypertension indicate that electrical activation of the carotid sinus baroreflex can reduce arterial pressure (AP) for more than a year. To examine whether the electrical stimulation from one baroreflex system impedes normal short-term AP regulation via another unstimulated baroreflex system, we electrically stimulated the left aortic depressor nerve (ADN) while estimating the dynamic characteristics of the carotid sinus baroreflex in anesthetized normotensive Wistar-Kyoto (WKY; n = 8) rats and spontaneously hypertensive rats (SHR; n = 7). Isolated carotid sinus regions were perturbed for 20 min using a Gaussian white noise signal with a mean of 120 mmHg for WKY and 160 mmHg for SHR. Tonic ADN stimulation (2 Hz, 10 V, and 0.1-ms pulse width) decreased mean sympathetic nerve activity (73.4 +/- 14.0 vs. 51.6 +/- 11.3 arbitrary units in WKY, P = 0.012; and 248.7 +/- 33.9 vs. 181.1 +/- 16.6 arbitrary units in SHR, P = 0.018) and mean AP (90.8 +/- 6.6 vs. 81.2 +/- 5.4 mmHg in WKY, P = 0.004; and 128.6 +/- 9.8 vs. 114.7 +/- 10.3 mmHg in SHR, P = 0.009). The slope of dynamic gain in the neural arc transfer function from carotid sinus pressure to sympathetic nerve activity was not different between trials with and without the ADN stimulation (12.55 +/- 0.93 vs. 13.03 +/- 1.28 dB/decade in WKY, P = 0.542; and 17.37 +/- 1.01 vs. 17.47 +/- 1.64 dB/decade in SHR, P = 0.946). These results indicate that the tonic ADN stimulation does not significantly modify the dynamic characteristics of the carotid sinus baroreflex.

DOI： 10.1152/ajpregu.00530.2016

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：SPRINGER JAPAN KK  

Cavopulmonary assist (CPA) for failing Fontan patients remains a challenging issue in the clinical setting. To evaluate the effectiveness of a partial CPA from the inferior vena cava (IVC) to the pulmonary artery (PA), we performed a theoretical analysis using a computational model of the Fontan circulation. Cardiac chambers and vascular systems were described as the time-varying elastance model and the modified three-element Windkessel model, respectively. A rotational pump described as a non-linear function was inserted between the IVC and the PA. When pulmonary vascular resistance index varied from 2.1 to 5.9 Wood units m(2), the partial CPA maintained cardiac index as efficiently as total CPA and markedly reduced the IVC pressure compared with total CPA. However, the partial CPA increased the superior vena cava pressure substantially. The modification from total to partial CPA is potentially an effective alternative in failing Fontan patients suffering from high IVC pressure.

DOI： 10.1007/s12576-015-0422-3

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：SPRINGER  

A hybrid procedure combining bilateral pulmonary artery banding with ductal stenting has recently been used as stage I palliation for hypoplastic left heart syndrome. However, the advantage of the hybrid procedure over the Norwood procedure on ventricular energetics remains unclear. To clarify this, we performed a computational analysis with a combination of time-varying elastance chamber model and modified three-element Windkessel vascular model. Although mean pulmonary artery (PA) pressure, pulmonary flow, and oxygen saturation were almost equivalent with the Norwood procedure, the hybrid procedure delivered higher systolic and lower diastolic systemic arterial pressures compared to the Norwood procedure with right ventricle (RV) to PA shunt. As a result, the hybrid procedure yielded increased systolic pressure-volume area and impaired mechanical efficiency. Therefore, the hybrid procedure has probably no advantage on ventricular energetics compared to the Norwood procedure with a RV-PA shunt.

DOI： 10.1007/s00380-014-0604-6

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：PERGAMON-ELSEVIER SCIENCE LTD  

Aims: To assess the acute effects of intravenous azelnidipine, a third-generation L-type calcium channel blocker, on sympathetic outflow from the central nervous system and to compare the effects of intravenous azelnidipine with those of intravenous nifedipine.Main methods: In anesthetized Wistar Kyoto rats, carotid sinus baroreceptor regions were isolated. Changes in sympathetic nerve activity (SNA) and arterial pressure (AP) in response to a stepwise baroreceptor pressure input were examined before and during intravenous nifedipine or azelnidipine (for each: 100 mu g/kg bolus followed by 300 mu g/kg/h infusion, n = 6).Key findings: Nifedipine significantly reduced the range of the AP response from 76.8 +/- 7.4 to 45.4 +/- 7.0 mm Hg (P <0.01) but did not affect the range of the SNA response (from 84.4 +/- 5.1 to 85.9 +/- 10.2%) or the SNA maximum gain (from 2.26 +/- 0.28 to 2.35 +/- 0.55%/mm Hg). Similarly, azelnidipine significantly reduced the range of the AP response from 62.4 +/- 3.9 to 31.4 +/- 4.1 mm Hg (P <0.01) but did not affect the range of the SNA response (from 71.2 +/- 5.5 to 74.9 +/- 7.2%) or the SNA maximum gain (from 1.64 +/- 0.17 to 2.08 +/- 0.26%/mm Hg).Significance: A depressor dose of nifedipine or azelnidipine does not have an acute sympathoinhibitory effect in normotensive Wistar Kyoto rats even when the level of SNA was varied over the entire operating range of the carotid sinus baroreflex. (C) 2015 Elsevier Inc. All rights reserved.

DOI： 10.1016/j.lfs.2015.01.024

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：JAPANESE CIRCULATION SOC  

Background: There is ongoing controversy over whether neural or peripheral factors are the predominant cause of hypertension. The closed-loop negative feedback operation of the arterial baroreflex hampers understanding of how arterial pressure (AP) is determined through the interaction between neural and peripheral factors.Methods and Results: A novel analysis of an isolated open-loop baroreceptor preparation to examine sympathetic nervous activity (SNA) and AP responses to changes in carotid sinus pressure (CSP) in adult spontaneously hypertensive rats (SHR) and normotensive Wistar Kyoto rats (WKY) was conducted. In the neural arc (CSP-SNA relationship), the midpoint pressure (128.9 +/- 3.8 vs. 157.9 +/- 8.1 mmHg, P<0.001) and the response range of SNA to CSP (90.5 +/- 3.7 vs. 115.4 +/- 7.6%/mmHg, P=0.011) were higher in SHR. In the peripheral arc (SNA-AP relationship), slope and intercept did not differ. A baroreflex equilibrium diagram was obtained by depicting neural and peripheral arcs in a pressure-SNA plane with rescaled SNA (% in WKY). The operating-point AP (111.3 +/- 4.4 vs. 145.9 +/- 5.2 mmHg, P<0.001) and SNA (90.8 +/- 3.2 vs. 125.1 +/- 6.9% in WKY, P<0.001) were shifted towards a higher level in SHR.Conclusions: The shift of the neural arc towards a higher SNA range indicated a predominant contribution to baroreflex resetting in SHR. Notwithstanding the resetting, the carotid sinus baroreflex in SHR preserved an ability to reduce AP if activated with a high enough pressure.

DOI： 10.1253/circj.CJ-14-1013

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：ELSEVIER SCIENCE BV  

An alpha(2A)-adrenergic agonistguanfacine improves autonomic imbalance in attention-deficit hyperactivity disorder, suggesting that it may be useful to correct autonomic imbalance in chronic heart failure (CHF) patients. To investigate the effects of guanfacine on cardiac autonomic nerve activities, a microdialysis technique was applied to anesthetized rabbit heart. Acetylcholine (ACh) and norepinephrine (NE) concentrations in atrial dialysates were measured as indices of cardiac autonomic nerve activities. Guanfacine at a dose of 100 mu g/kg significantly decreased heart rate and increased dialysate ACh concentration without decreasing sympathetic NE release. Guanfacine may be useful for vagal activation therapy in CHF patients. (C) 2014 Elsevier B.V. All rights reserved.

DOI： 10.1016/j.autneu.2014.11.010

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掲載種別：研究論文（学術雑誌）  

The arterial baroreflex system may be divided into the neural arc (from pressure input to efferent sympathetic nerve activity) and the peripheral arc (from sympathetic nerve activity to arterial pressure). In rabbits, the baroreflex neural arc reveals derivative characteristics in the frequency range below 0.8 Hz and high-cut characteristics above 0.8 Hz. To examine such high-cut characteristics are also present in rats, we isolated the carotid sinus regions in anesthetized rats (n = 5) and imposed a Gaussian white noise input with a switching interval of 50 ms. The transfer function of the baroreflex neural arc showed derivative characteristics in the frequency range from 0.1 to 1.3 Hz and high-cut characteristics above 1.3 Hz in rats. These results indicate that the baroreflex neural arc possesses high-cut characteristics in rats as well as in rabbits, which may contribute to preserving baroreflex gain against pulsatile pressure.

DOI： 10.11239/jsmbe.52.O-406

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：FRONTIERS RESEARCH FOUNDATION  

The baroreflex is a key mechanism involved in the control of arterial pressure (AP) during orthostasis in humans. However, the baroreflex is a closed-loop feedback system, from baroreceptor pressure input to systemic AP and therefore requires open-loop experiments to identify its system characteristics. The requirement limits our ability to identify baroreflex system characteristics in humans. Open-loop research in animals has revealed dynamic and static characteristics of the two baroreflex subsystems: the neural and peripheral arcs. The neural arc, from baroreceptor pressure input to sympathetic nerve activity (SNA), has high-pass dynamic characteristics, indicating that more rapid change in input AP causes greater response in SNA. In contrast, the peripheral arc, from SNA input to systemic AP has low-pass characteristics. Orthostasis increases the gain of the neural arc, which compensates for the lower transfer gain of the peripheral arc and in turn maintains total baroreflex function. Here, I discuss the possibility that baroreflex subsystem characteristics identified in animals can be applicable to the human sympathetic response to orthostasis, with a focus on loading speed-dependence of orthostatic sympathetic activation.

DOI： 10.3389/fphys.2014.00256

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：JAPANESE CIRCULATION SOC  

Background: To identify a pharmacological agent that can selectively activate cardiac vagus nerve for potential use in vagal activation therapy against heart failure, the effects of medetomidine on autonomic nerve activities in both the heart and stomach were examined.Methods and Results: In anesthetized rabbits, microdialysis probes were implanted into both the right atrial and gastric walls. Dialysate acetylcholine (ACh) and norepinephrine (NE) concentrations were measured by high-performance liquid chromatography. First, the effects of 100 mu g/kg of intravenous medetomidine on vagal ACh and sympathetic NE releases were examined. Medetomidine significantly increased cardiac ACh release (4.7 +/- 1.1 to 7.8 +/- 0.9 nmol/L, P<0.05), but suppressed gastric ACh release (8.0 +/- 2.6 to 3.5 +/- 1.5 nmol/L, P<0.01). In contrast, medetomidine suppressed both cardiac and gastric NE releases. Second, the effects of medetomidine on ACh releases induced by electrical vagus nerve stimulation (VNS; 10 Hz) were examined. Electrical VNS significantly increased both cardiac (6.7 +/- 1.2 to 14.8 +/- 1.8 nmol/L, P<0.01) and gastric (3.8 +/- 0.8 to 181.3 +/- 65.6 nmol/L, P<0.01) ACh releases. Medetomidine did not alter the VNS-induced increases in ACh release.Conclusions: Medetomidine suppresses both cardiac and gastric sympathetic nerve activities. In contrast, medetomidine activates cardiac vagus nerve but inhibits gastric vagal activity. Medetomidine might be one of the potential pharmacological agents for vagal activation therapy against heart failure without the risk of gastric adverse effects.

DOI： 10.1253/circj.CJ-13-1456

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記述言語：英語   出版者・発行元：LIPPINCOTT WILLIAMS & WILKINS  

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掲載種別：研究論文（学術雑誌）  

Aim: To examine whether sympathetic afferent stimulation (SAS) inhibits central vagal activation induced by α2-adrenergic stimulation. Methods: In anaesthetized Wistar-Kyoto rats, a cardiac microdialysis technique was applied to the left ventricle, and the effect of α2-adrenergic stimulation by medetomidine on myocardial interstitial acetylcholine (ACh) levels was examined in the absence (n = 6) or the presence (n = 6) of SAS delivered from the left stellate ganglion. The effect of electrical vagal efferent stimulation on myocardial interstitial ACh release was also examined in the absence or the presence of SAS (n = 6). Results: Intravenous medetomidine (0.1 mg kg-1) significantly increased myocardial interstitial ACh levels in the absence of SAS (from 1.95 ± 0.79 to 3.36 ± 1.61 nm, P < 0.05), but not in the presence of SAS (from 1.67 ± 0.67 to 2.01 ± 0.78 nm). In contrast, electrical vagal nerve stimulation increased myocardial interstitial ACh level to the same degree regardless of SAS (from 1.66 ± 0.16 to 3.93 ± 0.72 nm without SAS vs. 4.05 ± 0.89 nm with SAS). Conclusion: Sympathetic afferent stimulation inhibited medetomidine-induced ACh release, but not electrical stimulation-induced ACh release, suggesting that SAS inhibited medetomidine-induced vagal activation via central mechanisms. While central vagal activation by α2-adrenergic agonists could be an alternative to electrical vagal activation, blocking sympathetic afferent input may be important to increase the efficacy of α2-adrenergic agonists in enhancing vagal nerve activity. © 2013 Scandinavian Physiological Society.

DOI： 10.1111/apha.12123

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：PERGAMON-ELSEVIER SCIENCE LTD  

Aims: Cilnidipine is a unique Ca2+ channel blocker that inhibits both L-type and N-type Ca2+ channels. The present study aimed to assess the effects of intravenous cilnidipine on sympathetic outflow and sympathetic arterial pressure (AP) and heart rate (HR) regulations.Main methods: Carotid sinus baroreceptor regions were isolated from the systemic circulation in anesthetized and vagotomized Wistar Kyoto rats. Changes in efferent sympathetic nerve activity (SNA), AP and HR in response to a stepwise input of carotid sinus pressure were examined before and during intravenous cilnidipine administration (30 mu g/kg bolus + 100 mu g kg(-1) h(-1) infusion, n = 6).Key findings: Cilnidipine significantly reduced the AP response range (from 68.0 +/- 10.2 to 34.6 +/- 4.1 mmHg, P = 0.007) but did not affect the SNA response range (from 90.4 +/- 10.3 to 84.7 +/- 9.5%, P = 0.297) or the HR response range (from 50.4 +/- 10.1 to 48.1 +/- 6.2 beats/min, P = 0.719).Significance: Cilnidipine, at a depressor dose used in the present study, does not acutely suppress sympathetic outflow from the central nervous system. Also, it spared the sympathetic HR response, suggesting that N-type Ca2+ channel blocking action at the cardiac sympathetic nerve endings may be a modest one. (C) 2013 Elsevier Inc. All rights reserved.

DOI： 10.1016/j.lfs.2013.05.004

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掲載種別：研究論文（学術雑誌）  

Aim: To examine whether dynamic characteristics of the peripheral vagal control of heart rate (HR) are altered in chronic heart failure (CHF). Methods: The right vagal nerve was electrically stimulated according to a binary white noise signal, and the transfer function from vagal nerve stimulation (VNS) to HR was estimated in the frequency range from 0.01 to 1 Hz in five control rats and five CHF rats under anaesthetized conditions. The rate of VNS was changed among 10, 20 and 40 Hz. Results: A multiple linear regression analysis indicated that the increase in the VNS rate augmented the ratio of the high-frequency (HF) gain to the steady-state gain in the control group but not in the CHF group. As a result, the dynamic gain of the transfer function in the frequencies near 1 Hz decreased more in the CHF group than in the control group. Conclusion: Changes in the dynamic characteristics of the peripheral vagal control of HR may contribute to the manifestation of decreased HF components of HR variability observed in CHF. © 2012 The Authors. Acta Physiologica © 2012 Scandinavian Physiological Society.

DOI： 10.1111/apha.12055

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記述言語：英語   出版者・発行元：SPRINGER JAPAN KK  

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記述言語：英語   出版者・発行元：LIPPINCOTT WILLIAMS & WILKINS  

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掲載種別：研究論文（学術雑誌）  

Aim: To elucidate the abnormality of vagal control in spontaneously hypertensive rats (SHR) by measuring left ventricular myocardial interstitial acetylcholine (ACh) release in response to α2-adrenergic stimulation as an index of in vivo vagal nerve activity. Methods: A cardiac microdialysis technique was applied to the rat left ventricle in vivo, and the effect of α2-adrenergic stimulation by medetomidine or electrical vagal nerve stimulation on myocardial interstitial ACh levels was examined in normotensive Wistar-Kyoto rats (WKY) and SHR under anaesthetized conditions. Results: Intravenous medetomidine (0.1 mg kg-1) significantly increased the ACh levels in WKY (from 2.4 ± 0.6 to 4.2 ± 1.3 nmol L-1, P < 0.05, n = 7) but not in SHR (from 2.5 ± 0.7 to 2.7 ± 0.7 nmol L-1, n = 7). In contrast, electrical vagal nerve stimulation increased the ACh levels in both WKY (from 1.0 ± 0.4 to 2.9 ± 0.9 nmol L-1, P < 0.001, n = 6) and SHR (from 0.9 ± 0.2 to 2.2 ± 0.4 nmol L-1, P < 0.001, n = 6). Intravenous administration of medetomidine (0.1 mg kg-1) did not affect the vagal nerve stimulation-induced ACh release in either WKY or SHR. Conclusion: Medetomidine-induced central vagal activation was impaired in SHR, whereas peripheral vagal control of ACh release was preserved. In addition to abnormal sympathetic control, vagal control by the central nervous system may be impaired in SHR. © 2012 The Authors Acta Physiologica © 2012 Scandinavian Physiological Society.

DOI： 10.1111/j.1748-1716.2012.02439.x

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：JAPANESE CIRCULATION SOC  

Background: Although alpha(2)-adrenergic agonists have been reported to induce a vagal-dominant condition through suppression of sympathetic nerve activity, there is little direct evidence that they directly increase cardiac vagal nerve activity. Using a cardiac microdialysis technique, we investigated the effects of medetomidine, an alpha(2)-adrenergic agonist, on norepinephrine (NE) and acetylcholine (ACh) release from cardiac nerve endings.Methods and Results: A microdialysis probe was implanted into the right atrial wall near the sinoatrial node in anesthetized rabbits and perfused with Ringer's solution containing eserine. Dialysate NE and ACh concentrations were measured using high-performance liquid chromatography. Both 10 and 100 mu g/kg of intravenous medetomidine significantly decreased mean blood pressure (BP) and the dialysate NE concentration, but only 100 mu g/kg of medetomidine enhanced ACh release. Combined administration of medetomidine and phenylephrine maintained mean BP at baseline level, and augmented the medetomidine-induced ACh release. When we varied the mean BP using intravenous administration of phenylephrine, treatment with medetomidine significantly steepened the slope of the regression line between mean BP and log ACh concentration.Conclusions: Medetomidine increased ACh release from cardiac vagal nerve endings and augmented baroreflex control of vagal nerve activity. (Circ J 2012; 76: 152-159)

DOI： 10.1253/circj.CJ-11-0574

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：SPRINGER  

We have reported that minute ventilation [Vover dot(E)] and end- tidal CO2 tension [P-ETCO2] are determined by the interaction between central controller and peripheral plant properties. During exercise, the controller curve shifts upward with unchanged central chemoreflex threshold to compensate for the plant curve shift accompanying increased metabolism. This effectively stabilizes PETCO2 within the normal range at the expense of exercise hyperpnea. In the present study, we investigated how endurancetrained athletes reduce this exercise hyperpnea. Nine exercise- trained and seven untrained healthy males were studied. To characterize the controller, we induced hypercapnia by changing the inspiratory CO2 fraction with a background of hyperoxia and measured the linear PETCO2 Vover dot(E) relation [Vover dot(E) = S (P-ETCO2 - B)]. To characterize the plant, we instructed the subjects to alter Vover dot(E) voluntarily and measured the hyperbolic Vover dot(E) - P-ETCO2 relation (P-ETCO2 A/Vover dot(E) + C). We characterized these relations both at rest and during light exercise. Regular exercise training did not affect the characteristics of either controller or plant at rest. Exercise stimulus increased the controller gain (S) both in untrained and trained subjects. On the other hand, the P-ETCO2 - intercept (B) during exercise was greater in trained than in untrained subjects, indicating that exercise- induced upward shift of the controller property was less in trained than in untrained subjects. The results suggest that the additive exercise drive to breathe was less in trained subjects, without necessarily a change in central chemoreflex threshold. The hyperbolic plant property shifted rightward and upward during exercise as predicted by increased metabolism, with little difference between two groups. The Vover dot(E) during exercise in trained subjects was 21% lower than that in untrained subjects (P < 0.01). These results indicate that an adaptation of the controller, but not that of plant, contributes to the attenuation of exercise hyperpnea at an iso- metabolic rate in trained subjects. However, whether training induces changes in neural drive originating from the central nervous system, afferents from the working limbs, or afferents from the heart, which is additive to the chemoreflex drive to breathe, cannot be determined from these results.

DOI： 10.1007/s00421-011-1968-2

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記述言語：英語   掲載種別：研究論文（国際会議プロシーディングス）   出版者・発行元：IEEE  

The dynamic characteristics of vagal heart rate control can be approximated by a first-order low-pass filter with pure dead time in rabbits. However, this model may not necessarily be the best approximation of the vagal transfer function of the heart rate control in rats, because a flatter portion exists in the gain plot above approximately 0.3 Hz. We developed a new model that includes a frequency-independent gain term to reproduce the flatter portion of the gain plot seen in the vagal transfer function in rats. The inclusion of the new term increased the coefficient of determination in an external validation of the linear regression relationship between measured and predicted heart rate responses to vagal stimulation, and made the slope of the regression line closer to unity. The parameters of mathematical transfer functions were determined in both the frequency and time domains. The frequency-domain fitting provided a set of parameters that was also able to reproduce the time-domain step response reasonably well. In contrast, the time-domain fitting provided a set of parameters that reproduced the frequency-domain transfer function only up to 0.2 Hz. Determination of proper model parameters was crucial for the development of a new model to describe the dynamic heart rate response to vagal stimulation in rats.

DOI： 10.1109/EMBC.2012.6346797

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記述言語：英語   出版者・発行元：LIPPINCOTT WILLIAMS & WILKINS  

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：SPRINGER TOKYO  

When the Norwood procedure is conducted for the hypoplastic left heart syndrome using a non-valved right ventricle (RV) to pulmonary artery (PA) shunt, diastolic regurgitation from PA to RV may have an adverse effect on postoperative hemodynamics. In this study, we examined the impact of the diastolic regurgitation on ventricular energetics by computational analysis using a combination of a time-varying elastance chamber model and a modified three-element Windkessel vascular model. This study revealed that use of the valved or non-valved RV-PA shunt eliminated pulmonary over-circulation which was observed when using the systemic to pulmonary artery shunt (modified Blalock-Taussig shunt). Although the valved RV-PA shunt improved pulmonary blood supply and consequently increased pulmonary artery flow and oxygen saturation compared to the non-valved RV-PA shunt, the non-valved RV-PA shunt improved ventricular energetics in spite of the presence of PA to RV regurgitation.

DOI： 10.1007/s12576-011-0166-7

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：PERGAMON-ELSEVIER SCIENCE LTD  

Aims: To examine whether moderate efferent vagal nerve stimulation (VNS) attenuates the carotid sinus baroreflex-mediated arterial pressure (AP) regulation via its antagonism to the sympathetic system.Main methods: Carotid sinus baroreceptor regions were isolated from the systemic circulation in eight anesthetized and vagotomized rats. A staircase-wise input was imposed on carotid sinus pressure (CSP) with or without efferent VNS (20 Hz, 2 ms, 1-4 V), while the responses in AP, heart rate (HR), and splanchnic sympathetic nerve activity (SNA) were measured.Key findings: A multiple linear regression analysis indicated that VNS decreased the minimum HR in the CSP-HR relationship by 58.2 +/- 4.9 beats/min (P<0.01) from its reference value of 387.0 +/- 5.8 beats/min. Although VNS significantly decreased an intercept of the SNA-AP relationship, it did not affect parameters of the CSP-AP relationship or the CSP-SNA relationship significantly. The operating-point AP of the baroreflex was decreased by 2.8 +/- 1.0 mm Hg (P<0.01) during VNS, which was less than 3% of the reference value of 117.7 +/- 1.2 mm Hg.Significance: VNS, at an intensity of decreasing HR by approximately 13%, does not acutely attenuate the baroreflex-mediated sympathetic AP regulation. (C) 2011 Elsevier Inc. All rights reserved.

DOI： 10.1016/j.lfs.2011.07.026

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：ELSEVIER SCIENCE BV  

Although central ghrelin has cardioprotective effect through inhibiting sympathetic nerve activity, the effects of central ghrelin on cardiac vagal nerve remain unknown. We investigated the effects of centrally administered ghrelin on cardiac autonomic nerve activities using microdialysis technique. A microdialysis probe was implanted in the right atrial wall adjacent to the sinoatrial node of an anesthetized rabbit and was perfused with Ringer's solution containing a cholinesterase inhibitor, eserine. After injection of ghrelin (1 nmol) into the right lateral cerebral ventricle, norepinephrine (NE) and acetylcholine (ACh) concentrations in the dialysate samples were measured as indices of NE and ACh release from nerve endings to the sinoatrial node using high-performance liquid chromatography. Heart rate was 270 +/- 4 bpm at baseline and decreased gradually after ghrelin injection to 234 +/- 9 bpm (P<0.01) at 60-80 min, followed by gradual recovery. Dialysate ACh concentration was 5.5 +/- 0.8 nM at baseline and increased gradually after ghrelin injection to 8.8 +/- 1.2 nM (P<0.01) at 60-80 min: the concentration started to decrease gradually from 100 to 120 min after injection reaching 5.6 +/- 0.8 nM at 160-180 min. Central ghrelin did not change mean arterial pressure or dialysate NE concentration. The elevated dialysate ACh concentration declined rapidly after transection of cervical vagal nerves. These results indicate that centrally administered ghrelin activates cardiac vagal nerve. (C) 2011 Elsevier B.V. All rights reserved.

DOI： 10.1016/j.autneu.2011.04.001

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：WILEY  

Non-technical summaryThe arterial baroreflex is a closed-loop, negative feedback control system that senses baroreceptor pressure and controls systemic arterial pressure (AP) to attenuate perturbations in AP. The total arc of the baroreflex consists of two subsystems: the neural (baroreceptor pressure input to sympathetic nerve activity (SNA)) and peripheral (SNA input to AP) arcs. We show that although the spontaneous baroreflex transfer function obtained by closed-loop analysis has been believed to represent the neural arc function, it is inappropriate for system identification of the neural arc but is essentially appropriate for the peripheral arc under resting condition, when compared with open-loop transfer functions that have good predictabilities of time-series output dynamics from input signals. Our results indicate that in the spontaneous baroreflex system under closed-loop conditions, the peripheral arc (feedforward) function predominates over the neural arc (feedback) function, probably because of the SNA component that is independent of the baroreceptor pressure input.Although the dynamic characteristics of the baroreflex system have been described by baroreflex transfer functions obtained from open-loop analysis, the predictability of time-series output dynamics from input signals, which should confirm the accuracy of system identification, remains to be elucidated. Moreover, despite theoretical concerns over closed-loop system identification, the accuracy and the predictability of the closed-loop spontaneous baroreflex transfer function have not been evaluated compared with the open-loop transfer function. Using urethane and alpha-chloralose anaesthetized, vagotomized and aortic-denervated rabbits (n = 10), we identified open-loop baroreflex transfer functions by recording renal sympathetic nerve activity (SNA) while varying the vascularly isolated intracarotid sinus pressure (CSP) according to a binary random (white-noise) sequence (operating pressure +/- 20 mmHg), and using a simplified equation to calculate closed-loop-spontaneous baroreflex transfer function while matching CSP with systemic arterial pressure (AP). Our results showed that the open-loop baroreflex transfer functions for the neural and peripheral arcs predicted the time-series SNA and AP outputs from measured CSP and SNA inputs, with r2 of 0.8 +/- 0.1 and 0.8 +/- 0.1, respectively. In contrast, the closed-loop-spontaneous baroreflex transfer function for the neural arc was markedly different from the open-loop transfer function (enhanced gain increase and a phase lead), and did not predict the time-series SNA dynamics (r2; 0.1 +/- 0.1). However, the closed-loop-spontaneous baroreflex transfer function of the peripheral arc partially matched the open-loop transfer function in gain and phase functions, and had limited but reasonable predictability of the time-series AP dynamics (r2, 0.7 +/- 0.1). A numerical simulation suggested that a noise predominantly in the neural arc under resting conditions might be a possible mechanism responsible for our findings. Furthermore, the predictabilities of the neural arc transfer functions obtained in open-loop and closed-loop conditions were validated by closed-loop pharmacological (phenylephrine and nitroprusside infusions) pressure interventions. Time-series SNA responses to drug-induced AP changes predicted by the open-loop transfer function matched closely the measured responses (r2, 0.9 +/- 0.1), whereas SNA responses predicted by closed-loop-spontaneous transfer function deviated greatly and were the nverse of measured responses (r, -0.8 +/- 0.2). These results indicate that although the spontaneous baroreflex transfer function obtained by closed-loop analysis has been believed to represent the neural arc function, it is inappropriate for system identification of the neural arc but is essentially appropriate for the peripheral arc under resting conditions, when compared with open-loop analysis.

DOI： 10.1113/jphysiol.2011.203455

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：AMER PHYSIOLOGICAL SOC  

We examined the transfer function of autonomic heart rate (HR) control in anesthetized sedentary and exercise-trained (16 wk, treadmill for 1 h, 5 times/wk at 15 m/min and 15-degree grade) rats for comparison to HR variability assessed in the conscious resting state. The transfer function from sympathetic stimulation to HR response was similar between groups (gain, 4.2 +/- 1.5 vs. 4.5 +/- 1.5 beats.min(-1).Hz(-1); natural frequency, 0.07 +/- 0.01 vs. 0.08 +/- 0.01 Hz; damping coefficient, 1.96 +/- 0.55 vs. 1.69 +/- 0.15; and lag time, 0.7 +/- 0.1 vs. 0.6 +/- 0.1 s; sedentary vs. exercise trained, respectively, means +/- SD). The transfer gain from vagal stimulation to HR response was 6.1 +/- 3.0 in the sedentary and 9.7 +/- 5.1 beats.min(-1).Hz(-1) in the exercise-trained group (P = 0.06). The corner frequency (0.11 +/- 0.05 vs. 0.17 +/- 0.09 Hz) and lag time (0.1 +/- 0.1 vs. 0.2 +/- 0.1 s) did not differ between groups. When the sympathetic transfer gain was averaged for very-low-frequency and low-frequency bands, no significant group effect was observed. In contrast, when the vagal transfer gain was averaged for very-low-frequency, low-frequency, and high-frequency bands, exercise training produced a significant group effect (P < 0.05 by two-way, repeated-measures ANOVA). These findings suggest that, in the frequency domain, exercise training augments the dynamic HR response to vagal stimulation but not sympathetic stimulation, regardless of the frequency bands.

DOI： 10.1152/ajpregu.00768.2010

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：ELSEVIER SCIENCE BV  

The modalities of acupuncture can be broadly classified into manual acupuncture (MA) and electroacupuncture (EA). Although MA has been reported to cause winding of tissue around the needle and subsequent activation of the sensory mechanoreceptors and nociceptors, the sensory mechanisms of acupuncture stimulation are not fully understood. To test the hypothesis that the involvement of the mechanoreceptors in the sensory mechanism is different in MA and EA, we examined the effects of a stretch-activated channel blocker gadolinium on the hemodynamic responses to hind limb MA and EA in anesthetized rats (n = 9). Gadolinium significantly attenuated the MA-induced bradycardic response (-22 +/- 5 vs. -10 +/- 3 bpm, P < 0.05) and tended to attenuate the MA-induced depressor response (-30 +/- 5 vs. 18 4 mm Hg, P = 0.06). On the other hand, gadolinium significantly attenuated both the EA-induced bradycardic (-22 +/- 5 vs. 9 4 bpm, P < 0.01) and depressor responses (-32 +/- 6 vs. 15 5 mm Hg, P < 0.01). These results indicate that the mechanoreceptors are involved in the sensory mechanisms for both MA and EA. (C) 2010 Elsevier B.V. All rights reserved.

DOI： 10.1016/j.autneu.2010.11.004

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：AMER PHYSIOLOGICAL SOC  

Kawada T, Shimizu S, Kamiya A, Sata Y, Uemura K, Sugimachi M. Dynamic characteristics of baroreflex neural and peripheral arcs are preserved in spontaneously hypertensive rats. Am J Physiol Regul Integr Comp Physiol 300: R155-R165, 2011. First published November 3, 2010; doi:10.1152/ajpregu.00540.2010.-Although baroreceptors are known to reset to operate in a higher pressure range in spontaneously hypertensive rats (SHR), the total profile of dynamic arterial pressure (AP) regulation remains to be clarified. We estimated open-loop transfer functions of the carotid sinus baroreflex in SHR and Wistar Kyoto (WKY) rats. Mean input pressures were set at 120 (WKY120 and SHR120) and 160 mmHg (SHR160). The neural arc transfer function from carotid sinus pressure to efferent splanchnic sympathetic nerve activity (SNA) revealed derivative characteristics in both WKY and SHR. The slope of dynamic gain (in decibels per decade) between 0.1 and 1 Hz was not different between WKY120 (10.1 +/- 1.0) and SHR120 (10.4 +/- 1.1) but was significantly greater in SHR160 (13.2 +/- 0.8, P < 0.05 with Bonferroni correction) than in SHR120. The peripheral arc transfer function from SNA to AP showed low-pass characteristics. The slope of dynamic gain (in decibels per decade) did not differ between WKY120 (-34.0 +/- 1.2) and SHR120 (-31.4 +/- 1.0) or between SHR120 and SHR160 (-32.8 +/- 1.3). The total baroreflex showed low-pass characteristics and the dynamic gain at 0.01 Hz did not differ between WKY120 (0.91 +/- 0.08) and SHR120 (0.84 +/- 0.13) or between SHR120 and SHR160 (0.83 +/- 0.11). In both WKY and SHR, the declining slope of dynamic gain was significantly gentler for the total baroreflex than for the peripheral arc, suggesting improved dynamic AP response in the total baroreflex. In conclusion, the dynamic characteristics of AP regulation by the carotid sinus baroreflex were well preserved in SHR despite significantly higher mean AP.

DOI： 10.1152/ajpregu.00540.2010

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記述言語：英語   掲載種別：研究論文（国際会議プロシーディングス）   出版者・発行元：IEEE  

The carotid sinus baroreflex is one of the most important negative feedback systems to stabilize arterial pressure. Although static characteristics of the carotid sinus baroreflex can be assessed by using a stepwise input protocol under baroreflex open-loop conditions, the step duration has been determined empirically. In the present study, we examined the effects of different time windows (5-10, 15-20, 25-30, 35-40, 45-50, and 55-60 s) on the static characteristics estimated by using a 60-s stepwise input protocol in 10 anesthetized rats. Based on the results, we compared the static characteristics between actual 60-s and 20-s stepwise input protocols. Most of the parameters of the static characteristics did not differ significantly between the 60-s and 20-s stepwise input protocols, suggesting that the open-loop baroreflex static characteristics can be estimated by using a stepwise input with the step duration as short as 20 s in normal rats.

DOI： 10.1109/IEMBS.2011.6090155

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：SPRINGER JAPAN KK  

The internal thoracic artery (ITA) is harvested by either the pedicled or the skeletonized technique in coronary artery bypass grafting (CABG), with no clear advantage of one technique over the other. We compared graft flow between the pedicled and skeletonized ITA grafts while varying myocardial oxygen demand. CABG was performed to the left anterior descending artery in five anesthetized dogs using a pedicled ITA graft and the graft was subsequently skeletonized. Graft flow was measured during stepwise electrical stimulation of the stellate ganglion. The baseline graft flow before sympathetic stimulation was higher in skeletonized (27.8 +/- 1.9 ml/min) than that in pedicled ITA grafts (22.6 +/- 2.7 ml/min) (P < 0.05). In both ITA grafts, however, graft flow increased to a similar level during sympathetic stimulation that doubled the double product, correlating with the double product. Based on these results, we conclude that metabolic demand can override the potential difference in sympathetic vasoconstriction in both pedicled and skeletonized ITA grafts.

DOI： 10.1007/s12576-010-0109-8

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記述言語：英語   出版者・発行元：LIPPINCOTT WILLIAMS & WILKINS  

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：WILEY-BLACKWELL  

We estimated the transfer function of autonomic heart rate (HR) control by using random binary sympathetic or vagal nerve stimulation in anaesthetized rats. The transfer function from sympathetic stimulation to HR response approximated a second-order, low-pass filter with a lag time (gain, 4.29 +/- 1.55 beats min-1 Hz-1; natural frequency, 0.07 +/- 0.03 Hz; damping coefficient, 1.96 +/- 0.64; and lag time, 0.73 +/- 0.12 s). The transfer function from vagal stimulation to HR response approximated a first-order, low-pass filter with a lag time (gain, 8.84 +/- 4.51 beats min-1 Hz-1; corner frequency, 0.12 +/- 0.06 Hz; and lag time, 0.12 +/- 0.08 s). These results suggest that the dynamic characteristics of HR control by the autonomic nervous system in rats are similar to those of larger mammals.

DOI： 10.1113/expphysiol.2010.053090

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：ELSEVIER SCIENCE BV  

Although large conductance Ca2+-activated K+ (BK) channels play an important role in determining vascular tone, their role in the efferent cardiac vagal system remains to be elucidated. In anesthetized rabbits (n =9), acetylcholine (ACh) was measured at the right atrium near the sinoatrial node by a cardiac microdialysis technique, and the ACh release in response to electrical stimulation of the cervical preganglionic vagal nerves was examined. Local administration of a BK channel blocker iberiotoxin (2 mu M) through a dialysis fiber increased the stimulation-induced ACh release from 7.6 +/- 2.7 to 9.0 +/- 3.2 nM (P<0.05). Addition of intravenous administration of iberiotoxin (0.11 mg/body) did not increase the stimulation-induced ACh release further (10.8 +/- 4.4 nM). These results indicate that the BK channels play an inhibitory role in the vagal ACh release to the sinoatrial node. (C) 2010 Elsevier B.V. All rights reserved.

DOI： 10.1016/j.autneu.2010.04.003

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：SPRINGER JAPAN KK  

We estimated open-loop dynamic characteristics of the carotid sinus baroreflex in normal control rats and chronic heart failure (CHF) rats after myocardial infarction. First, the neural arc transfer function from carotid sinus pressure to splanchnic sympathetic nerve activity (SNA) and its corresponding step response were examined. Although the steady-state response was attenuated in CHF, the negative peak response and the time to peak did not change significantly, suggesting preserved neural arc dynamic characteristics. Next, the peripheral arc transfer function from SNA to arterial pressure (AP) and its corresponding step response were examined. The steady-state response and the initial slope were reduced in CHF, suggesting impaired end-organ responses. In a simulation study based on the dynamic and static characteristics, the percent recovery of AP was reduced progressively as the size of disturbance increased in CHF, suggesting that a reserve for AP buffering is lost in CHF despite relatively maintained baseline AP.

DOI： 10.1007/s12576-010-0096-9

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：SPRINGER JAPAN KK  

One and a half ventricle repair (1.5VR) is a surgical option for hypoplastic right ventricle (RV). The benefits of this procedure compared to biventricular repair (2VR) or Fontan operation remain unsettled. To compare postoperative hemodynamics, we performed a theoretical analysis using a computational model based on lumped-parameter state-variable equations. We varied the RV stiffness constant (B (RV)) to simulate the various RV hypoplasia, and estimated hemodynamics for a given B (RV). With B (RV) < 150% of normal, cardiac output was the largest in 2VR. With B (RV) > 150%, cardiac output became larger in 1.5VR than in 2VR. With B (RV) > 250%, RV end-diastolic volume was almost the same between 1.5VR and 2VR, and a rapid increase in atrial pressure precluded the use of 1.5VR. These results indicate that the beneficial effect of 1.5VR depends on the RV stiffness constant. Determination of management strategy should not only be based on the morphologic parameters but also on the physiological properties of RV.

DOI： 10.1007/s12576-010-0086-y

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：ELSEVIER SCIENCE BV  

We assessed in vivo interstitial norepinephrine (NE) levels at the sinoatrial node in rabbits, using microdialysis technique. A dialysis probe was implanted adjacent to the sinoatrial node of an anesthetized rabbit and dialysate was sampled during sympathetic nerve stimulation. Atrial dialysate NE concentration correlated well with heart rate. Desipramine significantly increased dialysate NE concentrations both before and during sympathetic nerve stimulation compared with the absence of desipramine. However, desipramine did not affect the relation between heart rate and dialysate NE concentration. These results suggest that atrial dialysate NE level reflects the relative change of NE concentration in the synaptic cleft. Microdialysis is a powerful tool to assess in vivo interstitial NE levels at the sinoatrial node. (C) 2009 Elsevier B.V. All rights reserved.

DOI： 10.1016/j.autneu.2009.08.017

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記述言語：英語   出版者・発行元：SPRINGER TOKYO  

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記述言語：英語   掲載種別：研究論文（国際会議プロシーディングス）   出版者・発行元：IEEE  

In our extended Guyton's model, the ability of heart to pump blood is characterized by a cardiac output curve and the ability of vasculature to pool blood by a venous return surface. These intersect in a three-dimensional coordinate system at the operating right atrial pressure, left atrial pressure, and cardiac output. The baseline cardiac output curve and venous return surface and their changes after volume change would predict new hemodynamics. The invasive methods needed to precisely characterize cardiac output curve and venous return surface led us to aim at estimating cardiac output curve and venous return surface from a single hemodynamic measurement. Using the average values for two logarithmic function parameters, and for two slopes of a surface, we were able to estimate cardiac output curve and venous return surface. The estimated curve and surface predicted new hemodynamics after volume change precisely.

DOI： 10.1109/IEMBS.2010.5626268

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記述言語：英語   出版者・発行元：SPRINGER TOKYO  

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：SPRINGER TOKYO  

Although an acute arterial pressure (AP) elevation induced by intravenous angiotensin II (ANG II) does not inhibit sympathetic nerve activity (SNA) compared to an equivalent AP elevation induced by phenylephrine, there are conflicting reports as to how circulating ANG II affects the baroreflex control of SNA. Because most studies have estimated the baroreflex function under closed-loop conditions, differences in the rate of input pressure change and the magnitude of pulsatility may have biased the estimation results. We examined the effects of intravenous ANG II (10 mu g kg(-1) h(-1)) on the open-loop system characteristics of the carotid sinus baroreflex in anesthetized and vagotomized rats. Carotid sinus pressure (CSP) was raised from 60 to 180 mmHg in increments of 20 mmHg every minute, and steady-state responses in systemic AP, splanchnic SNA and heart rate (HR) were analyzed using a four-parameter logistic function. ANG II significantly increased the minimum values of AP (67.6 +/- 4.6 vs. 101.4 +/- 10.9 mmHg, P < 0.01), SNA (33.3 +/- 5.4 vs. 56.5 +/- 11.5%, P < 0.05) and HR (391.1 +/- 13.7 vs. 417.4 +/- 11.5 beats/min, P < 0.01). ANG II, however, did not attenuate the response range for AP (56.2 +/- 7.2 vs. 49.7 +/- 6.2 mmHg), SNA (69.6 +/- 5.7 vs. 78.9 +/- 9.1%) or HR (41.7 +/- 5.1 vs. 51.2 +/- 3.8 beats/min). The maximum gain was not affected for AP(1.57 +/- 0.28 vs. 1.20 +/- 0.25), SNA(1.94 +/- 0.34 vs. 2.04 +/- 0.42%/mmHg) or HR (1.11 +/- 0.12 vs. 1.28 +/- 0.19 beats min(-1) mmHg(-1)). It is concluded that high levels of circulating ANG II did not attenuate the response range of open-loop carotid sinus baroreflex control for AP, SNA or HR in anesthetized and vagotomized rats.

DOI： 10.1007/s12576-009-0055-5

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：PERGAMON-ELSEVIER SCIENCE LTD  

Aims: To examine endogenous acetylcholine (ACh) release in the rabbit left ventricle during acute ischemia, ischemic preconditioning and electrical vagal stimulation.Main methods: We measured myocardial interstitial ACh levels in the rabbit left ventricle using a cardiac microdialysis technique. In Protocol 1 (n = 6), the left circumflex coronary artery (LCX) was occluded for 30 min and reperfused for 30 min. In Protocol 2 (n = 5), the LCX was temporarily occluded for 5 min. Ten minutes later, the LCX was occluded for 30 min and reperfused for 30 min. In Protocol 3 (n = 5), bilateral efferent vagal nerves were stimulated at 20 Hz and 40 Hz (10 V, 1-ms pulse duration).Key findings: In Protocol 1, a 30-min coronary occlusion increased the ACh level from 0.39 +/- 0.15 to 7.0 +/- 2.2 nM (mean +/- SE, P<0.01). In Protocol 2, a 5-min coronary occlusion increased the ACh level from 0.33 +/- 0.07 to 0.75 +/- 0.11 nM (P<0.05). The ACh level returned to 0.48 +/- 0.10 nM during the interval. After that, a 30-min coronary occlusion increased the ACh level to 2.4 +/- 0.49 nM (P<0.01),In Protocol 3,vagal stimulation at 20 Hz and 40 Hz increased the ACh level from 0.29 +/- 0.06 to 1.23 +/- 0.48 (P<0.05) and 2.44 +/- 1.13 nM (P<0.01), respectively.Significance: Acute ischemia significantly increased the ACh levels in the rabbit left ventricle, which appeared to exceed the vagal stimulation-induced ACh release. Brief ischemia as short as 5 min can also increase the ACh level, suggesting that endogenous ACh release can be a trigger for ischemic preconditioning. (C) 2009 Published by Elsevier Inc.

DOI： 10.1016/j.lfs.2009.08.015

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：AMER PHYSIOLOGICAL SOC  

Kamiya A, Kawada T, Shimizu S, Iwase S, Sugimachi M, Mano T. Slow head-up tilt causes lower activation of muscle sympathetic nerve activity: loading speed dependence of orthostatic sympathetic activation in humans. Am J Physiol Heart Circ Physiol 297: H53-H58, 2009. First published May 15, 2009; doi:10.1152/ajpheart.00260.2009.-Many earlier human studies have reported that increasing the tilt angle of head-up tilt (HUT) results in greater muscle sympathetic nerve activity (MSNA) response, indicating the amplitude dependence of sympathetic activation in response to orthostatic stress. However, little is known about whether and how the inclining speed of HUT influences the MSNA response to HUT, independent of the magnitude of HUT. Twelve healthy subjects participated in passive 30 HUT tests at inclining speeds of 1 (control), 0.1 (slow), and 0.0167 (very slow) per second. We recorded MSNA (tibial nerve) by microneurography and assessed nonstationary time-dependent changes of R-R interval variability using a complex demodulation technique. MSNA averaged over every 10 tilt angle increased during inclination from 0 to 30, with smaller increases in the slow and very slow tests than in the control test. Although a 3-min MSNA overshoot after reaching 30 HUT was observed in the control test, no overshoot was detected in the slow and very slow tests. In contrast with MSNA, increases in heart rate during the inclination and after reaching 30 were similar in these tests, probably because when compared with the control test, greater increases in plasma epinephrine counteracted smaller autonomic responses in the very slow test. These results indicate that slower HUT results in lower activation of MSNA, suggesting that HUT-induced sympathetic activation depends partially on the speed of inclination during HUT in humans.

DOI： 10.1152/ajpheart.00260.2009

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：ELSEVIER SCIENCE BV  

To directly monitor vagal acetylcholine (ACh) release into the sinoatrial node, which regulates heart rate, we implanted a microdialysis probe in the right atrium near the sinoatrial node and in the right ventricle of anesthetized rabbits, and perfused with Ringer's solution containing eserine. (1) Electrical stimulation of right or left cervical vagal nerve decreased atrial rate and increased dialysate ACh concentration in the right atrium in a frequency-dependent manner. Compared to left vagal stimulation, right vagal nerve stimulation decreased atrial rate to a greater extent at all frequencies, and increased dialysate ACh concentration to a greater extent at 10 and 20 Hz. However, dialysate ACh concentration in the right atrium correlated well with atrial rate independent of whether electrical stimulation was applied to the right or left vagal nerve (atrial rate = 304 - 131 x log[ACh], R(2) = 0.77). (2) Right or left vagal nerve stimulation at 20 Hz decreased atrial rate and increased dialysate ACh concentrations in both the right atrium (right, 17.9 +/- 4.0 nM; left, 7.9 +/- 1.4 nM) and right ventricle (right, 0.9 +/- 0.3 nM; left, 1.0 +/- 0.4 nM). However, atrial dialysate ACh concentrations were significantly higher than ventricular concentrations, while ventricular dialysate ACh concentrations were not significantly different between right and left vagal nerve stimulation. (3) The response of ACh release to right and left vagal nerve stimulation was abolished by intravenous administration of a ganglionic blocker, hexamethonium bromide. In conclusion, ACh concentration in dialysate from the right atrium, sampled by microdialysis, is a good marker of ACh release from postganglionic vagal nerves to the sinoatrial node. (C) 2009 Elsevier B.V. All rights reserved.

DOI： 10.1016/j.autneu.2009.02.006

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：JAPANESE CIRCULATION SOC  

Background: Autonomic neural intervention is a promising tool for modulating the Circulatory system thereby treating some cardiovascular diseases.Methods and Results: In 8 pentobarbital-anesthetized cats, it was examined whether the arterial pressure (AP) could be controlled by acupuncture-like hind-limb electrical stimulation (HES). With a 0.5-ms Pulse width, HES monotonically reduced AP as the stimulus current increased from I to 5 mA, suggesting that the stimulus current could be a primary control variable. In contrast, the depressor effect of HES showed a nadir approximately 10 Hz in the frequency range between 1 and 100Hz. Dynamic characteristics of the AP response to HES approximated a second-order low-pass filter with dead time (gain: -10.2 +/- 1.6mmHg/mA, natural frequency: 0.040 +/- 0.004Hz, damping ratio 1.80 +/- 0.24, dead time: 1.38 +/- 0.13s, mean +/- SE). Based on these dynamic characteristics, a servo-controlled HES system was developed. When a target AP value was set at 20 mmHg below the baseline AP, the time required for the AP response to reach 90% of the target level was 38 +/- 10s. The steady-state error between the measured and target AP values was 1.3 +/- 0.1 mmHg.Conclusions: Autonomic neural intervention by acupuncture-like HES might provide an additional modality to quantitatively control the circulatory system. (Circ J 2009; 73: 851-859)

DOI： 10.1253/circj.CJ-08-1058

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：AMER PHYSIOLOGICAL SOC  

Kawada T, Mizuno M, Shimizu S, Uemura K, Kamiya A, Sugimachi M. Angiotensin II disproportionally attenuates dynamic vagal and sympathetic heart rate controls. Am J Physiol Heart Circ Physiol 296: H1666-H1674, 2009. First published February 27, 2009; doi:10.1152/ajpheart.01041.2008.-To better understand the pathophysiological role of angiotensin II (ANG II) in the dynamic autonomic regulation of heart rate (HR), we examined the effects of intravenous administration of ANG II (10 mu g.kg(-1).h(-1)) on the transfer function from vagal or sympathetic nerve stimulation to HR in anesthetized rabbits with sinoaortic denervation and vagotomy. In the vagal stimulation group (n = 7), we stimulated the right vagal nerve for 10 min using binary white noise (0-10 Hz). The transfer function from vagal stimulation to HR approximated a first-order low-pass filter with pure delay. ANG II attenuated the dynamic gain from 7.6 +/- 0.9 to 5.8 +/- 0.9 beats.min(-1).Hz(-1) (means +/- SD; P < 0.01) without affecting the corner frequency or pure delay. In the sympathetic stimulation group (n = 7), we stimulated the right postganglionic cardiac sympathetic nerve for 20 min using binary white noise (0-5 Hz). The transfer function from sympathetic stimulation to HR approximated a second-order low-pass filter with pure delay. ANG II slightly attenuated the dynamic gain from 10.8 +/- 2.6 to 10.2 +/- 3.1 beats.min(-1).Hz(-1) (P = 0.049) without affecting the natural frequency, damping ratio, or pure delay. The disproportional suppression of the dynamic vagal and sympathetic regulation of HR would result in a relative sympathetic predominance in the presence of ANG II. The reduced high-frequency component of HR variability in patients with cardiovascular diseases, such as myocardial infarction and heart failure, may be explained in part by the peripheral effects of ANG II on the dynamic autonomic regulation of HR.

DOI： 10.1152/ajpheart.01041.2008

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記述言語：英語   掲載種別：研究論文（国際会議プロシーディングス）   出版者・発行元：IEEE  

The ultimate goal of disease treatment is to control the biological system beyond the native regulation to combat pathological process. To maximize the advantage of drugs, we attempted to pharmacologically control the biological system at will, e.g., control multiple hemodynamic variables with multiple cardiovascular drugs. A comprehensive physiological cardiovascular model enabled us to evaluate cardiovascular properties (pump function, vascular resistance, and blood volume) and the feedback control of these properties. In 12 dogs, with dobutamine (5 +/- 3 mu g.kg(-1).min(-1)), nitroprusside (4 +/- 2 mu g.kg(-1).min(-1) dextran (2 +/- 2 ml.kg(-1)), and furosemide (10 mg in one, 20 mg in one), rapid, sufficient and stable control of pump function, vascular resistance and blood volume resulted in similarly quick and stable control of blood pressure, cardiac output and left atrial pressure in 5 +/- 7, 7 +/- 5, and 12 +/- 10 minutes, respectively. These variables remained stable for 60 minutes (RMS 4 +/- 3 mmHg, 5 +/- 2 ml.min(-1).kg(-1) 0.8 +/- 0.6 mmHg, respectively).

DOI： 10.1109/IEMBS.2009.5334417

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記述言語：英語   掲載種別：研究論文（国際会議プロシーディングス）   出版者・発行元：IEEE  

Comprehensive understanding of hemodynamics remains a challenge even for expert cardiologists, partially due to a lack of an appropriate macroscopic model. We attempted to amend three major problems of Guyton's conceptual model (unknown left atrial pressure, unilateral heart damage, blood redistribution) and developed a comprehensive macroscopic model of hemodynamics that provides quantitative information. We incorporated a third axis of left atrial pressure, resulting in a 3D coordinate system. Pump functions of left and right heart are expressed by an integrated cardiac output curve, and the capacitive function of total vasculature by a venous return surface. The equations for both the cardiac output curve and venous return surface would facilitate precise diagnosis (especially evaluation of blood volume) and choice of appropriate treatments, including application to autopilot systems.

DOI： 10.1109/IEMBS.2009.5335017

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：ELSEVIER SCIENCE BV  

Electroacupuncture (EA) is known to affect hemodynamics through modulation of efferent sympathetic nerve activity (SNA), however. possible regional differences ill the SNA response to EA remains to be examined. Based oil the discordance between arterial blood pressure and heart rate changes during EA, we hypothesized that regional differences Would occur among SNAs during EA. To test this hypothesis, we compared changes in cardiac and renal SNAs in response to 1-min EA (10 Hz or 2 Hz) of a hind limb in adult cats anesthetized with pentobarbital sodium. Renal SNA remained decreased for 1 min during EA (P < 0.01 for both 10 Hz and 2Hz). In contrast, cardiac SNA tented to decrease only in the beginning of EA. It increased during the end of EA (P < 0.05 for 2 Hz) and further increased after the end of EA (P < 0.01 both for 10 Hz and 2 Hz). There was a quasi-linear relationship between renal and cardiac SNAs with a slope of 0.69 (i.e., renal SNA was more suppressed than cardiac SNA) during the last 10 s of EA. The discrepancy between the renal and cardiac SNAs persisted after sinoaortic denervation and vagotomy. In conclusion, EA evokes differential patterns of SNA responses and changes the relationship between cardiac and renal SNAs. (C) 2008 Elsevier B.V. All rights reserved.

DOI： 10.1016/j.autneu.2008.09.002

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：SPRINGER JAPAN KK  

Although muscarinic K+ (K-ACh) channels contribute to a rapid heart rate (HR) response to vagal stimulation, whether background sympathetic tone affects the HR control via the K-ACh channels remains to be elucidated. In seven anesthetized rabbits with sinoaortic denervation and vagotomy, we estimated the dynamic transfer function of the HR response by using random binary vagal stimulation (0-10 Hz). Tertiapin, a selective K-ACh channel blocker, decreased the dynamic gain (to 2.3 +/- 0.9 beats. min(-1).Hz(-1), from 4.6 +/- 1.1, P < 0.01, mean +/- SD) and the corner frequency (to 0.05 +/- 0.01 Hz, from 0.26 +/- 0.04, P < 0.01). Under 5 Hz tonic cardiac sympathetic stimulation (CSS), tertiapin decreased the dynamic gain (to 3.6 +/- 1.0 beats.min(-1).Hz(-1), from 7.3 +/- 1.1, P < 0.01) and the corner frequency (to 0.06 +/- 0.02 Hz, from 0.23 +/- 0.06, P < 0.01). Two-way analysis of variance indicated significant interaction between the tertiapin and CSS effects on the dynamic gain. In contrast, no significant interactions were observed between the tertiapin and CSS effects on the corner frequency and the lag time, In conclusion, although a cyclic AMP-dependent mechanism has been well established, an accentuated antagonism also occurred in the direct effect of ACh via the KACh channels. The rapidity of the HR response obtained by the KACh channel pathway was robust during the accentuated antagonism.

DOI： 10.2170/physiolsci.RP011508

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：AMER PHYSIOLOGICAL SOC  

Miyamoto T, Kawada T, Yanagiya Y, Akiyama T, Kamiya A, Mizuno M, Takaki H, Sunagawa K, Sugimachi M. Contrasting effects of presynaptic alpha(2)-adrenergic autoinhibition and pharmacologic augmentation of presynaptic inhibition on sympathetic heart rate control. Am J Physiol Heart Circ Physiol 295: H1855-H1866, 2008. First published August 29, 2008; doi:10.1152/ajpheart.522.2008. - Presynaptic alpha(2)-adrenergic receptors are known to exert feedback inhibition on norepinephrine release from the sympathetic nerve terminals. To elucidate the dynamic characteristics of the inhibition, we stimulated the right cardiac sympathetic nerve according to a binary white noise signal while measuring heart rate (HR) in anesthetized rabbits (n = 6). We estimated the transfer function from cardiac sympathetic nerve stimulation to HR and the corresponding step response of HR, with and without the blockade of presynaptic inhibition by yohimbine (1 mg/kg followed by 0.1 mg . kg(-1) . h(-1) iv). We also examined the effect of the alpha(2)-adrenergic receptor agonist clonidine (0.3 and 1.5 mg . kg(-1) . h(-1) iv) in different rabbits (n = 5). Yohimbine increased the maximum step response (from 7.2 +/- 0.8 to 12.2 +/- 1.7 beats/min, means +/- SE, P < 0.05) without significantly affecting the initial slope (0.93 +/- 0.23 vs. 0.94 +/- 0.22 beats . min(-1) . s(-1)). Higher dose but not lower dose clonidine significantly decreased the maximum step response (from 6.3 +/- 0.8 to 6.8 +/- 1.0 and 2.8 +/- 0.5 beats/min, P < 0.05) and also reduced the initial slope (from 0.56 +/- 0.07 to 0.51 +/- 0.04 and 0.22 +/- 0.06 beats . min(-1) . s(-1), P < 0.05). Our findings indicate that presynaptic alpha(2)-adrenergic autoinhibition limits the maximum response without significantly compromising the rapidity of effector response. In contrast, pharmacologic augmentation of the presynaptic inhibition not only attenuates the maximum response but also results in a sluggish effector response.

DOI： 10.1152/ajpheart.522.2008

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：AMER PHYSIOLOGICAL SOC  

Although the muscle mechanoreflex is one of the pressor reflexes during exercise, its interaction with dynamic characteristics of the arterial baroreflex remains to be quantitatively analyzed. In anesthetized, vagotomized, and aortic-denervated rabbits (n = 7), we randomly perturbed isolated carotid sinus pressure (CSP) using binary white noise while recording renal sympathetic nerve activity (SNA) and arterial pressure (AP). We estimated the transfer functions of the baroreflex neural arc (CSP to SNA) and peripheral arc (SNA to AP) under conditions of control and muscle stretch of the hindlimb (5 kg of tension). The muscle stretch increased the dynamic gain of the neural arc while maintaining the derivative characteristics [gain at 0.01 Hz: 1.0 +/- 0.2 vs. 1.4 +/- 0.6 arbitrary units (au)/mmHg, gain at 1 Hz: 1.7 +/- 0.6 vs. 2.7 +/- 1.4 au/mmHg; P < 0.05, control vs. stretch]. In contrast, muscle stretch did not affect the peripheral arc. In the time domain, muscle stretch augmented the steady-state response at 50 s (- 1.1 +/- 0.3 vs. -1.7 +/- 0.7 au; P < 0.05, control vs. stretch) and negative peak response (-2.1 +/- 0.5 vs. -3.1 +/- 1.5 au; P < 0.05, control vs. stretch) in the SNA step response. A simulation experiment using the results indicated that the muscle mechanoreflex would accelerate the closed-loop AP regulation via the arterial baroreflex.

DOI： 10.1152/ajpheart.00023.2008

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：ELSEVIER IRELAND LTD  

Although an importance of vasoconstrictor skin sympathetic nerve activity (SNA) in control of cutaneous circulation is widely recognized, the decoding rule that translate dynamic fluctuations of vasoconstrictor skin SNA into skin blood flow is not fully understood. In 10 male subjects who rested in supine position under normothermic condition, we measured skin blood flow index (by laser-Doppler flowmetry) at the dorsum pedis, and vasoconstrictor skin SNA (by microneurography) that was confirmed to innervate the same region as the flow index. We determined the transfer and coherence functions from the neural activity input to the flow and quantified the contribution and predictability from the input to output by system engineering technique. The results showed that in frequency-domain analysis, the transfer function from vasoconstrictor skin SNA to skin blood flow had low-pass filter characteristics with 3.6 +/- 0.1 s of pure time delay. The coherence function was approximately 0.5 between 0.01 and 0.1 Hz and less above 0.1 Hz. In time-domain analysis, the predictability from the SNA to the skin blood flow was approximately 50%. These findings indicate that at normothermic rest, the decoding rule from vasoconstrictor skin SNA to skin blood flow of skin is characterized by low-pass filter with 3-4 s of pure time delay, and that the vasoconstrictor skin SNA contributes to a half of fluctuation of skin blood flow in the condition. The incomplete dependence of skin blood flow on vasoconstrictor skin SNA may confirm nonneural mechanisms to control cutaneous circulation even at normothermic rest. (c) 2008 Elsevier Ireland Ltd. All rights reserved.

DOI： 10.1016/j.neulet.2008.04.018

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：PHYSIOLOGICAL SOC JAPAN  

Maintenance of arterial pressure (AP) under orthostatic stress against gravitational fluid shift and pressure disturbance is of great importance. One of the mechanisms is that upright tilt resets steady-state baroreflex control to a higher sympathetic nerve activity (SNA). However, the dynamic feedback characteristics of the baroreflex system, a hallmark of fast-acting neural control, remain to be elucidated, In the present study, we tested the hypothesis that upright tilt resets the dynamic transfer function of the baroreflex neural arc to minify the pressure disturbance in total baroreflex control. Renal SNA and AP were recorded in ten anesthetized, vagotomized and aortic-denervated rabbits. Under baroreflex open-loop condition, isolated intracarotid sinus pressure (CSP) was changed according to a binary white noise sequence at operating pressure +/- 20 mmHg, while the animal was placed supine and at 60 degrees upright tilt. Regardless of the postures, the baroreflex neural (CSP to SNA) and peripheral (SNA to AP) arcs showed dynamic high-pass and low-pass characteristics, respectively. Upright tilt increased the transfer gain of the neural arc (resetting), decreased that of the peripheral arc, and consequently maintained the transfer characteristics of total baroreflex feedback system. A simulation study suggests that postural resetting of the neural arc would significantly increase the transfer gain of the total arc in upright position, and that in closed-loop baroreflex the resetting increases the stability of AP against pressure disturbance under orthostatic stress. In conclusion, upright tilt resets the dynamic transfer function of the baroreflex neural arc to minify the pressure disturbance in total baroreflex control.

DOI： 10.2170/physiolsci.RP004308

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記述言語：英語   出版者・発行元：FEDERATION AMER SOC EXP BIOL  

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記述言語：英語   掲載種別：研究論文（国際会議プロシーディングス）   出版者・発行元：IEEE  

Background: We have demonstrated that modification of autonomic balance by electrical vagal stimulation delays progression of cardiac dysfunction and cardiac remodeling, and prolongs survival in rats with severe heart failure. We have also shown that we were able to modify autonomic balance by electrical acupuncture at the acupoint of Zusanli, potentially applicable for the treatment of heart failure. We examined the effect of the acupuncture on the dynamic characteristics of the baroreflex system to exclude the possible deleterious effect on orthostatic tolerance.Method: In anesthetized 8 and 6 rabbits, we examined static and dynamic characteristics of baroreflex, respectively, with and without electrical acupuncture (1 Hz, 5 mA, and 5msec). Dynamic characteristics were examined by imposing pseudorandom binary changes in isolated carotid sinus pressure.Results: With the stimulation condition to decrease arterial blood pressure and sympathetic nerve activity (resulted form decreased response range of neural arc), either of the dynamic characteristics of neural arc or those of peripheral arc did not change by electrical acupuncture at Zusanli.Conclusion: We conclude that application of electrical acupuncture at Zusanli can suppress sympathetic nerve activity but does not affect the dynamic characteristics of the arterial baroreflex system, indicating no deleterious effect on orthostatic tolerance.

DOI： 10.1109/IEMBS.2008.4649577

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：AMER PHYSIOLOGICAL SOC  

Vagal nerve stimulation has been suggested to ameliorate left ventricular (LV) remodeling in heart failure. However, it is not known whether and to what degree vagal nerve stimulation affects matrix metalloproteinase (MMP) and tissue inhibitor of MMP (TIMP) in myocardium, which are known to play crucial roles in LV remodeling. We therefore investigated the effects of electrical stimulation of efferent vagal nerve on myocardial expression and activation of MMPs and TIMPs in a rabbit model of myocardial ischemia- reperfusion (I/R) injury. Anesthetized rabbits were subjected to 60 min of left coronary artery occlusion and 180 min of reperfusion with (I/R-VS, n = 8) or without vagal nerve stimulation (I/R, n = 7). Rabbits not subjected to coronary occlusion with (VS, n = 7) or without vagal stimulation (sham, n = 7) were used as controls. Total MMP-9 protein increased significantly after left coronary artery occlusion in I/R-VS and I/R to a similar degree compared with VS and sham values. Endogenous active MMP- 9 protein level was significantly lower in I/R-VS compared with I/R. TIMP-1 mRNA expression was significantly increased in I/R-VS compared with the I/R, VS, and sham groups. TIMP-1 protein was significantly increased in I/R-VS and VS compared with the I/R and sham groups. Cardiac microdialysis technique demonstrated that topical perfusion of acetylcholine increased dialysate TIMP-1 protein level, which was suppressed by coperfusion of atropine. Immunohistochemistry demonstrated a strong expression of TIMP-1 protein in cardiomyocytes around the dialysis probe used to perfuse acetylcholine. In conclusion, in a rabbit model of myocardial I/R injury, vagal nerve stimulation induced TIMP- 1 expression in cardiomyocytes and reduced active MMP-9.

DOI： 10.1152/ajpheart.00490.2007

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記述言語：英語   出版者・発行元：LIPPINCOTT WILLIAMS & WILKINS  

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：AMER PHYSIOLOGICAL SOC  

Vagal control of heart rate (HR) is mediated by direct and indirect actions of ACh. Direct action of ACh activates the muscarinic K+ ( KACh) channels, whereas indirect action inhibits adenylyl cyclase. The role of the KACh channels in the overall picture of vagal HR control remains to be elucidated. We examined the role of the KACh channels in the transfer characteristics of the HR response to vagal stimulation. In nine anesthetized sinoaortic-denerved and vagotomized rabbits, the vagal nerve was stimulated with a binary white-noise signal (0-10 Hz) for examination of the dynamic characteristic and in a step-wise manner ( 5, 10, 15, and 20 Hz/min) for examination of the static characteristic. The dynamic transfer function from vagal stimulation to HR approximated a firstorder, low-pass filter with a lag time. Tertiapin, a selective KACh channel blocker ( 30 nmol/kg iv), significantly decreased the dynamic gain from 5.0 +/- 1.2 to 2.0 +/- 0.6 ( mean +/- SD) beats . min(-1) . Hz(-1) ( P < 0.01) and the corner frequency from 0.25 +/- 0.03 to 0.06 +/- 0.01 Hz ( P < 0.01) without changing the lag time ( 0.37 +/- 0.04 vs. 0.39 +/- 0.05 s). Moreover, tertiapin significantly attenuated the vagal stimulation-induced HR decrease by 46 +/- 21, 58 +/- 18, 65 +/- 15, and 68 +/- 11% at stimulus frequencies of 5, 10, 15, and 20 Hz, respectively. We conclude that KACh channels contribute to a rapid HR change and to a larger decrease in the steady-state HR in response to more potent tonic vagal stimulation.

DOI： 10.1152/ajpheart.00368.2007

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：AMER SOC CLINICAL INVESTIGATION INC  

Grb2-associated binder (Gab) family of scaffolding adaptor proteins coordinate signaling cascades downstream of growth factor and cytokine receptors. In the heart, among EGF family members, neuregulin-1 beta (NRG-1 beta, a paracrine factor produced from endothelium) induced remarkable tyrosine phosphorylation of Gab 1 and Gab2 via erythroblastic leukemia viral oncogene (ErbB) receptors. We examined the role of Gab family proteins in NRG-1 beta/ErbB-mediated signal in the heart by creating cardiomyocyte-specific Gab1/Gab2 double knockout mice (DKO mice). Although DKO mice were viable, they exhibited marked ventricular dilatation and reduced contractility with aging. DKO mice showed high mortality after birth because of heart failure. In addition, we noticed remarkable endocardial fibroelastosis and increase of abnormally dilated vessels in the ventricles of DKO mice. NRG-1 beta induced activation of both ERK and AKT in the hearts of control mice but not in those of DKO mice. Using DNA microarray analysis, we found that stimulation with NRG-1 beta upregulated expression of an endothelium-stabilizing factor, angiopoietin 1, in the hearts of control mice but not in those of DKO mice, which accounted for the pathological abnormalities in the DKO hearts. Taken together, our observations indicated that in the NRG-1 beta/ErbB signaling, Gab1 and Gab2 of the myocardium are essential for both maintenance of myocardial function and stabilization of cardiac capillary and endocardial endothelium in the postnatal heart.

DOI： 10.1172/JCI30651

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記述言語：英語   出版者・発行元：FEDERATION AMER SOC EXP BIOL  

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記述言語：英語   出版者・発行元：ELSEVIER SCIENCE INC  

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：AMER PHYSIOLOGICAL SOC  

Although hypothermia is one of the most powerful modulators that can reduce ischemic injury, the effects of hypothermia on the function of the cardiac autonomic nerves in vivo are not well understood. We examined the effects of hypothermia on the myocardial interstitial norepinephrine ( NE) and ACh releases in response to acute myocardial ischemia and to efferent sympathetic or vagal nerve stimulation in anesthetized cats. We induced acute myocardial ischemia by coronary artery occlusion. Compared with normothermia (n = 8), hypothermia at 33 degrees C ( n = 6) suppressed the ischemia-induced NE release [ 63 nM (SD 39) vs. 18 nM ( SD 25), P < 0.01] and ACh release [11.6 nM ( SD 7.6) vs. 2.4 nM ( SD 1.3), P < 0.01] in the ischemic region. Under hypothermia, the coronary occlusion increased the ACh level from 0.67 nM (SD 0.44) to 6.0 nM (SD 6.0) (P < 0.05) and decreased the NE level from 0.63 nM ( SD 0.19) to 0.40 nM ( SD 0.25) ( P < 0.05) in the nonischemic region. Hypothermia attenuated the nerve stimulation-induced NE release from 1.05 nM ( SD 0.85) to 0.73 nM ( SD 0.73) ( P < 0.05, n = 6) and ACh release from 10.2 nM ( SD 5.1) to 7.1 nM ( SD 3.4) ( P < 0.05, n = 5). In conclusion, hypothermia attenuated the ischemia-induced NE and ACh releases in the ischemic region. Moreover, hypothermia also attenuated the nerve stimulation-induced NE and ACh releases. The Bezold-Jarisch reflex evoked by the left anterior descending coronary artery occlusion, however, did not appear to be affected under hypothermia.

DOI： 10.1152/japplphysiol.00622.2006

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記述言語：英語   掲載種別：研究論文（国際会議プロシーディングス）   出版者・発行元：IEEE  

Contribution of abnormal cardiovascular regulation to the maintenance and progression of heart failure has been repeatedly demonstrated. Besides the current therapeutic modalities, development of an additional therapeutic strategy is needed. We have been developing a bionic system, an artificial device designed for integration into native physiological systems. By communicating with the physiological regulatory system, we tried to not only restore lost function but also correct abnormal function. We have already shown that modification of autonomic balance by direct electrical vagal stimulation has inhibited cardiac remodeling, and improved survival in rats. Because the benefit of the correction of autonomic balance would be greatly enhanced if available by a less invasive method, we examined the possibility of modifying the autonomic balance by electrical acupuncture. The results indicated that electrical acupuncture resets the neural arc of the arterial baroreflex (SNA response range decreases from 144.0 +/- 35.0 to 112.6 +/- 9.2, p<0.005) and is able to attenuate sympathetic nerve activity.

DOI： 10.1109/IEMBS.2007.4353546

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：AMER PHYSIOLOGICAL SOC  

Effects of Ca2+ channel antagonists on nerve stimulation-induced and ischemia-induced myocardial interstitial acetylcholine release in cats. Am J Physiol Heart Circ Physiol 291: H2187-H2191, 2006. First published June 9, 2006; doi:10.1152/ajpheart.00175.2006. - Although an axoplasmic Ca2+ increase is associated with an exocytotic acetylcholine (ACh) release from the parasympathetic postganglionic nerve endings, the role of voltage-dependent Ca2+ channels in ACh release in the mammalian cardiac parasympathetic nerve is not clearly understood. Using a cardiac microdialysis technique, we examined the effects of Ca2+ channel antagonists on vagal nerve stimulation- and ischemia-induced myocardial interstitial ACh releases in anesthetized cats. The vagal stimulation-induced ACh release [22.4 nM (SD 10.6), n = 7] was significantly attenuated by local administration of an N-type Ca2+ channel antagonist omega-conotoxin GVIA [11.7 nM (SD 5.8), n = 7, P = 0.0054], or a P/Q-type Ca2+ channel antagonist omega-conotoxin MVIIC [3.8 nM (SD 2.3), n = 6, P = 0.0002] but not by local administration of an L-type Ca2+ channel antagonist verapamil [23.5 nM (SD 6.0), n = 5, P = 0.758]. The ischemia-induced myocardial interstitial ACh release [15.0 nM (SD 8.3), n = 8] was not attenuated by local administration of the L-, N-, or P/Q-type Ca2+ channel antagonists, by inhibition of Na+/Ca2+ exchange, or by blockade of inositol 1,4,5-trisphosphate [Ins(1,4,5)P-3] receptor but was significantly suppressed by local administration of gadolinium [2.8 nM (SD 2.6), n = 6, P = 0.0283]. In conclusion, stimulation- induced ACh release from the cardiac postganglionic nerves depends on the Nand P/Q-type Ca2+ channels (with a dominance of P/Q-type) but probably not on the L-type Ca2+ channels in cats. In contrast, ischemia-induced ACh release depends on nonselective cation channels or cation-selective stretch activated channels but not on L-, N-, or P/Q type Ca2+ channels, Na+/Ca2+ exchange, or Ins(1,4,5)P-3 receptor-mediated pathway.

DOI： 10.1152/ajpheart.00175.2006

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記述言語：英語   出版者・発行元：LIPPINCOTT WILLIAMS & WILKINS  

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記述言語：英語   出版者・発行元：CHURCHILL LIVINGSTONE INC MEDICAL PUBLISHERS  

DOI： 10.1016/j.cardfail.2006.08.082

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記述言語：英語   出版者・発行元：CHURCHILL LIVINGSTONE INC MEDICAL PUBLISHERS  

DOI： 10.1016/j.cardfail.2006.08.121

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：PHYSIOLOGICAL SOCIETY JAPAN  

Despite accumulating data of muscle sympathetic nerve activity (SNA) measured by human microneurography, whether neural discharges of muscle SNA correlates and coheres with those of other SNAs controlling visceral organs remains unclear. Further, how the baroreflex control of SNA affects the relations between these SNAs remains unknown. In urethane and alpha-chloralose anesthetized, vagotomized, and aortic-denervated rabbits, we recorded muscle SNA from the tibial nerve using microneurography and simultaneously recorded renal and cardiac SNAs. After isolating the carotid sinuses, we produced a baroreflex closed-loop condition by matching the isolated intracarotid sinus pressure (CSP) with systemic arterial pressure (CLOSE). We also fixed CSP at operating pressure (FIX) or altered CSP widely (WIDE: operating pressure 40 mmHg). Under these conditions, we calculated time-domain and frequency-domain measures of the correlation between muscle SNA and renal or cardiac SNAs. At CLOSE, muscle SNA resampled at 1 Hz correlated with both renal (r(2) = 0.71 +/- 0.04, delay = 0.10 +/- 0.004 s) and cardiac SNAs (r(2) = 0.58 +/- 0.03, delay = 0.13 +/- 0.004 s) at optimal delays. Moreover,muscle SNA at CLOSE strongly cohered with renal and cardiac SNAs(coherence > 0.8) at the autospectral peak frequencies, and weakly (0.4-0.5) at the remaining frequencies. Increasing the magnitude of CSP change from FIX to CLOSE and further to WIDE resulted in corresponding increases in correlation and coherence functions at nonpeak frequencies, and the coherence functions at peak frequencies remained high (> 0.8). In conclusion, muscle SNA correlates and coheres approximately with renal and cardiac SNAs under closed-loop baroreflex conditions. The arterial baroreflex is capable of potently homogenizing neural discharges of these SNAs by modulating SNA at the nonpeak frequencies of SNA autospectra.

DOI： 10.2170/physiolsci.RP009006

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：AMER PHYSIOLOGICAL SOC  

Although electroacupuncture reduces sympathetic nerve activity (SNA) and arterial pressure (AP), the effects of electroacupuncture on the arterial baroreflex remain to be systematically analyzed. We investigated the effects of electroacupuncture of Zusanli on the arterial baroreflex using an equilibrium diagram comprised of neural and peripheral arcs. In anesthetized, vagotomized, and aortic-denervated rabbits, we isolated carotid sinuses and changed intra-carotid sinus pressure (CSP) from 40 to 160 mmHg in increments of 20 mmHg/min while recording cardiac SNA and AP. Electroacupuncture of Zusanli was applied with a pulse duration of 5 ms and a frequency of 1 Hz. An electric current 10 times the minimal threshold current required for visible muscle twitches was used and was determined to be 4.8 +/- 0.3 mA. Electroacupuncture for 8 min decreased SNA and AP (n = 6). It shifted the neural arc (i.e., CSP-SNA relationship) to lower SNA but did not affect the peripheral arc (i.e., SNA-AP relationship) (n = 8). SNA and AP at the closed-loop operating point, determined by the intersection of the neural and peripheral arcs, decreased from 100 +/- 4 to 80 +/- 9 arbitrary units and from 108 +/- 9 to 99 +/- 8 mmHg (each P < 0.005), respectively. Peroneal denervation eliminated the shift of neural arc by electroacupuncture (n = 6). Decreasing the pulse duration to < 2.5 ms eliminated the effects of SNA and AP reduction. In conclusion, short-term electroacupuncture resets the neural arc to lower SNA, which moves the operating point toward lower AP and SNA under baroreflex closed-loop conditions.

DOI： 10.1152/ajpheart.00975.2005

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：SPRINGER JAPAN KK  

The sympathetic regulation of heart rate (HR) may be attained by neural and humoral factors. With respect to the humoral factor, plasma noradrenaline (NA) and adrenaline (Adr) can reportedly increase to levels approximately 10 times higher than resting level during severe exercise. Whether such high plasma NA or Adr interfered with the sympathetic neural regulation of HR remained unknown. We estimated the transfer function from cardiac sympathetic nerve stimulation (SNS) to HR in anesthetized and vagotomized rabbits. An intravenous administration of NA (n = 6) at 1 and 10 mu g.kg(-1).h(-1) increased plasma NA concentration (pg/ml) from a baseline level of 438 +/- 117 (mean +/- SE) to 974 +/- 106 and 6,830 +/- 917 (P < 0.01), respectively. The dynamic gain (bpm/Hz) of the transfer function did not change significantly (from 7.6 +/- 1.2 to 7.5 +/- 1.1 and 8.1 +/- 1.1), whereas mean HR (in bpm) during SNS slightly increased from 280 +/- 24 to 289 +/- 22 (P < 0.01) and 288 22 (P < 0.01). The intravenous administration of Adr (n = 6) at 1 and 10 mu g.kg(-1).h(-1) increased plasma Adr concentration (pg/ml) from a baseline level of 257 +/- 86 to 659 +/- 172 and 2,760 +/- 590 (P < 0.01), respectively. Neither the dynamic gain (from 8.0 +/- 0.6 to 8.4 +/- 0.8 and 8.2 +/- 1.0) nor the mean HR during SNS (from 274 +/- 13 to 275 +/- 13 and 274 +/- 13) changed significantly. In contrast, the intravenous administration of isoproterenol (n = 6) at 10 mu g.kg(-1).h(-1) significantly increased mean HR during SNS (from 278 +/- 11 to 293 +/- 9, P < 0.01) and blunted the transfer gain value at 0.0078 Hz (from 5.9 +/- 1.0 to 1.0 +/- 0.4, P < 0.01). In conclusion, high plasma NA or Adr hardly affected the dynamic sympathetic neural regulation of HR.

DOI： 10.2170/physiolsci.RP006006

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：ELSEVIER SCIENCE INC  

OBJECTIVES We examined how repolarization and depolarization abnormalities contribute to the development of extrasystoles and subsequent ventricular fibrillation (VF) in a model of the Brugada syndrome.BACKGROUND Repolarization and depolarization abnormalities have been considered to be mechanisms of the coved-type ST-segment elevation (Br-ugada-electrocardiogram [ECG]) and development of VF in the Brugada syndrome.METHODS We used high-resolution (256 x 256) optical mapping techniques to study arterially perfused canine right ventricular wedges (n = 20) in baseline and in the Brugada-ECG produced by administration of terfenadine (5 mu mol/l), pinacidil (2 mu mol/l), and pilsicainide (5 mu mol/l). We recorded spontaneous episodes of phase 2 re-entrant (P2R)-extrasystoles and subsequent self-terminating polymorphic ventricular tachycardia (PVT) or VF under the Brugada-ECG condition and analyzed the epicardial conduction velocity and action potential duration (APD) restitutions in each condition.RESULTS Forty-one episodes of spontaneous P2R-extrasystoles in the Brugada-ECG were successfully mapped in 9 of 10 preparations, and 33 of them were originated from the maximum gradient of repolarization (GR(max): 176 +/- 54 ms/mm) area in the epicardium, leading to PVT (n = 12) or VF (n = 5). The epicardial GR(max) was not different between PVT and VF. Wave-break during the first P2R-extrasystole produced multiple wavelets in all VF cases, whereas no wave-break or wave-break followed by wave collision and termination occurred in PVT cases. Moreover, conduction velocity restitution was shifted lower and APD restitution was more variable in VF cases than in PVT cases.CONCLUSIONS Steep repolarization gradient in the epicardium but not endocardium develops P2R-extrasystoles in the Brugada-ECG condition, which might degenerate into VF by further depolarization and repolarization abnormalities. (J Am Coll Cardiol 2006;47:2074-85) (c) 2006 by the American College of Cardiology Foundation.

DOI： 10.1016/j.jacc.2005.12.064

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掲載種別：研究論文（学術雑誌）  

Pharmacological support with inotropes and vasodilators to control decompensated hemodynamics requires strict monitoring of patient condition and frequent adjustments of drug infusion rates, which is difficult and time-consuming, especially in hemodynamically unstable patients. To overcome this difficulty, we have developed a novel automated drug delivery system for simultaneous control of systemic arterial pressure (AP), cardiac output (CO), and left atrial pressure (Pla). Previous systems attempted to directly control AP and CO by estimating their responses to drug infusions. This approach is inapplicable because of the difficulties to estimate simultaneous AP, CO, and Pla responses to the infusion of multiple drugs. The circulatory equilibrium framework developed previously (Uemura K, Sugimachi M, Kawada T, Kamiya A, Jin Y, Kashihara K, and Sunagawa K. Am J Physiol Heart Circ Physiol 286: H2376-H2385, 2004) indicates that AP, CO, and Pla are determined by an equilibrium of the pumping ability of the left heart (SL), stressed blood volume (V), and systemic arterial resistance (R). Our system directly controls SL with dobutamine, V with dextran/furosemide, and R with nitroprusside, thereby controlling the three variables. We evaluated the efficacy of our system in 12 anesthetized dogs with acute decompensated heart failure. Once activated, the system restored SL, V, and R within 30 min, resulting in the restoration of normal AP, CO, and Pla. Steady-state deviations from target values were small for AP [4.4 mmHg (SD 2.6)], CO [5.4 ml·min-1·kg-1 (SD 2.4)] and Pla [0.8 mmHg (SD 0.6)]. In conclusion, by directly controlling the mechanical determinants of circulation, our system has enabled simultaneous control of AP, CO, and Pla with good accuracy and stability. Copyright © 2006 the American Physiological Society.

DOI： 10.1152/japplphysiol.01206.2005

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記述言語：英語   掲載種別：研究論文（国際会議プロシーディングス）   出版者・発行元：IEEE  

Saving life of patients with acute life-threatening heart failure is a major challenge. One has to correct several fatal hemodynamic abnormalities at the same time within a limited time frame. The formulation of such complicated treatments enables the development of a system that can be used to save automatically lives of patients with acute heart failure, an autopilot system. To accomplish this, we established a comprehensive physiological cardiovascular model, on which we based the design of the autopilot system. By translating hemodynamics into cardiovascular parameters (pumping ability, vascular resistance, blood volume), and by controlling each of these with individual drugs, we were able to correct blood pressure, cardiac output, and left atrial pressure to the target values rapidly (5.2 +/- 6.6,6.8 +/- 4.6, and 11.7 +/- 9.8 minutes), stably, and simulataneously.

DOI： 10.1109/IEMBS.2006.259935

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記述言語：英語   掲載種別：研究論文（国際会議プロシーディングス）   出版者・発行元：IEEE  

Background. To understand the pathophysiologic basis of exercise hyperpnea in chronic heart failure (CHF), we have developed an experimental method quantitatively characterizing ventilatory regulation system in rats. An equilibrium diagram illustrates the characteristics of two subsytems, i.e., the central controller (arterial CO2 tension [Pa-CO2] to minute ventilation [V-E] relationship) and peripheral plant (V-E to Pa-CO2 relationship). In this study, we compared these between normal and CHIF rats at rest.Method: In anesthetized 6 postinfarction CHF rats and 6 normal rats, we induced hypercapnia by changing inspiratory CO2 fraction and measured the steady-state Pa-CO2 to V-E relation. We altered V-E by varying the level of artificial ventilation and measured the V-E to Pa-CO2 relation.Results: Central controller gain S was significantly lager in CHF rats, confirming clinical observation. The VE at rest (operating point) in CHF was 24 % larger; central hypersensitivity, however, contributed little (6 %) to this increase.Conclusion: Central hypersensitivity alone would not explain hyperpnea at rest in CHF rats. Considering the right and upward shift of V-E to Pa-CO2 relation, central hypersensitivity contributes more to hyperpnea during exercise. The potential difference between normal and CHF rats in exercise-induced changes in controller and plant should be examined to fully understand the mechanism of exercise hyperpnea and to develop a method to attenuate this.

DOI： 10.1109/IEMBS.2006.260268

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記述言語：英語   出版者・発行元：ELSEVIER IRELAND LTD  

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掲載種別：研究論文（学術雑誌）  

Background: There have so far been few reports on the static regulations of cerebral and systemic circulation during prolonged head-down bed rest (HDBR). Our aim was to investigate the time course changes in static cerebral and systemic circulation during 14 days of 6° HDBR. Material/Methods: Sixteen subjects participated in the HDBR study. The systolic, mean, and diastolic cerebral blood flow velocities (CBFVs) of the middle cerebral artery were measured using a transcranial Doppler technique. Cerebrovascular bed resistance indices, i.e., resistance index (RI), pulsatility index (PI), and estimated regional cerebrovascular resistance (CVRest) were calculated. The systemic cardiovascular functions, i.e., heart rate (HR), mean arterial pressure (MAP), left ventricular ejection time (LVET), stroke volume (SV), cardiac output (CO), and total peripheral resistance (TPR) were measured or calculated. Results: All CBFVs consistently showed significant decreases from the 2 nd day to the last day of the HDBR. The RI and PI showed a rising tendency throughout the HDBR. The CVRest showed significantly higher levels in the later half of the HDBR. The HR and MAP did not change during the HDBR. Conclusions: The adaptive process of cerebral circulation triggered by HDBR begins very early and leads to a new equilibrium within few days after the onset of HDBR. The alteration of static cerebral circulation with prolonged HDBR, i.e., lowered CBFVs and somewhat higher cerebrovascular bed resistance implies a reduction in the cerebral circulation, but it does not necessarily imply the impaired regulation of cerebral circulation.

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掲載種別：研究論文（学術雑誌）  

Despite accumulated knowledge on human baroreflex control of muscle sympathetic nerve activity (SNA), whether baroreflex control of muscle SNA parallels that of other SNAs, in particular renal and cardiac SNAs, remains unclear. Using urethane and α-chloralose-anesthetized, vagotomized and aortic-denervated rabbits (n = 10), we recorded muscle SNA from tibial nerve by microneurography, simultaneously with renal and cardiac SNAs by wire electrode. To produce a baroreflex open-loop condition, we isolated the carotid sinuses from systemic circulation and altered the intracarotid sinus pressure (CSP) according to a binary white noise sequence of operating pressure ± 20 mmHg (for investigating dynamic characteristics of baroreflex) or in stepwise 20-mmHg increments from 40 to 160 mmHg (for investigating static characteristics of baroreflex). Dynamic high-pass characteristics of baroreflex control of muscle SNA, assessed by the increasing slope of transfer gain, showed that more rapid change of arterial pressure resulted in greater response of muscle SNA to pressure change and that these characteristics were similar to cardiac SNA but greater than renal SNA. However, numerical simulation based on the transfer function shows that the differences in dynamic baroreflex control at various organs result in detectable differences among SNAs only when CSP changes at unphysiologically high rates (i.e., 5 mmHg/s). On the other hand, static reverse-sigmoid characteristics of baroreflex control of muscle SNA agreed well with those of renal or cardiac SNAs. In conclusion, dynamic-linear and static-nonlinear baroreflex control of muscle SNA is similar to that of renal and cardiac SNAs under physiological pressure change. Copyright © 2005 the American Physiological Society.

DOI： 10.1152/ajpheart.00642.2005

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掲載種別：研究論文（学術雑誌）  

Sympathetic activation during orthostatic stress is accompanied by a marked increase in low-frequency (LF, ∼0.1-Hz) oscillation of sympathetic nerve activity (SNA) when arterial pressure (AP) is well maintained. However, LF oscillation of SNA during development of orthostatic neurally mediated syncope remains unknown. Ten healthy subjects who developed head-up tilt (HUT)-induced syncope and 10 age-matched nonsyncopal controls were studied. Nonstationary time-dependent changes in calf muscle SNA (MSNA, microneurography), R-R interval, and AP (finger photoplethysmography) variability during a 15-min 60° HUT test were assessed using complex demodulation. In both groups, HUT during the first 5 min increased heart rate, magnitude of MSNA, LF and respiratory high-frequency (HF) amplitudes of MSNA variability, and LF and HF amplitudes of AP variability but decreased HF amplitude of R-R interval variability (index of cardiac vagal nerve activity). In the nonsyncopal group, these changes were sustained throughout HUT. In the syncopal group, systolic AP decreased from 100 to 60 s before onset of syncope; LF amplitude of MSNA variability decreased, whereas magnitude of MSNA and LF amplitude of AP variability remained elevated. From 60 s before onset of syncope, MSNA and heart rate decreased, index of cardiac vagal nerve activity increased, and AP further decreased to the level at syncope. LF oscillation of MSNA variability decreased during development of orthostatic neurally mediated syncope, preceding sympathetic withdrawal, bradycardia, and severe hypotension, to the level at syncope. Copyright © 2005 the American Physiological Society.

DOI： 10.1152/ajpheart.01027.2004

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掲載種別：研究論文（学術雑誌）  

Background - Despite the accumulated knowledge of human muscle sympathetic nerve activity (SNA) as measured by microneurography, whether muscle SNA parallels renal and cardiac SNAs remains unknown. Method and Results - In experiment 1, muscle (microneurography, tibial nerve), renal, and cardiac SNAs were recorded in anesthetized rabbits (n=6) while arterial pressure was changed by intravenous bolus injections of nitroprusside (3 μg/kg) followed by phenylephrine (3 μg/kg). In experiment 2, the carotid sinus region was vascularly isolated in anesthetized, vagotomized, and aorta-denervated rabbits (n=10). The 3 SNAs were recorded while intracarotid sinus pressure was increased stepwise from 40 to 160 mm Hg in 20-mm Hg increments maintained for 60 seconds each. Muscle SNA averaged over 1 minute was well correlated with renal (r=0.96±0.01, mean±SE) and cardiac (r=0.96±0.01) SNAs in experiment 1 (baroreflex closed-loop condition) and also with renal (r=0.97±0.01) and cardiac (r=0.97±0.01) SNAs in experiment 2 (baroreflex open-loop condition). Conclusions - Muscle SNA averaged over 1 minute parallels renal and cardiac SNAs in response to a forced baroreceptor pressure change. © 2005 American Heart Association, Inc.

DOI： 10.1161/CIRCULATIONAHA.104.493338

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掲載種別：研究論文（学術雑誌）  

Since humans are under ceaseless orthostatic stress, the mechanism to maintain arterial pressure AP) under orthostatic stress against gravitational fluid shift is of great importance. We hypothesized that (1) orthostatic stress resets the arterial baroreflex control of sympathetic nerve activity (SNA) to a higher SNA, and (2) resetting of the arterial baroreflex contributes to preventing postural hypotension. Renal SNA and AP were recorded in eight anaesthetized, vagotomized and aortic-denervated rabbits. Isolated intracarotid sinus pressure (CSP) was increased stepwise from 40 to 160 mmHg with increments of 20 mmHg (60 s for each CSP level) while the animal was placed supine and at 60 deg upright tilt. Upright tilt shifted the CSP-SNA relationship (the baroreflex neural arc) to a higher SNA, shifted the SNA-AP relationship (the baroreflex peripheral arc) to a lower AP, and consequently moved the operating point to marked high SNA while maintaining AP. A simulation study suggests that resetting in the neural arc would double the orthostatic activation of SNA and increase the operating AP in upright tilt by 10 mmHg, compared with the absence of resetting. In addition, upright tilt did not change the CSP-AP relationship (the baroreflex total arc). A simulation study suggests that although a downward shift of the peripheral arc could shift the total arc downward, resetting in the neural arc would compensate this fall and prevent the total arc from shifting downward to a lower AP. In conclusion, upright tilt increases SNA by resetting the baroreflex neural arc. This resetting may compensate for the reduced pressor responses to SNA in the peripheral cardiovascular system and contribute to preventing postural hypotension. © The Physiological Society 2005.

DOI： 10.1113/jphysiol.2005.086512

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掲載種別：研究論文（学術雑誌）  

Accurate prediction of cardiac output (CO), left atrial pressure (PLA), and right atrial pressure (PRA) is a prerequisite for management of patients with compromised hemodynamics. In our previous study (Uemura et al. Am J Physiol Heart Circ Physiol 286: H2376-H2385, 2004), we demonstrated a circulatory equilibrium framework, which permits the prediction of CO, PLA, and PRA once the venous return surface and integrated CO curve are known. Inasmuch as we also showed that the surface can be estimated from single-point CO, PLA, and PRA measurements, we hypothesized that a similar single-point estimation of the CO curve would enable us to predict hemodynamics. In seven dogs, we measured the PLA-CO and P RA-CO relations and derived a standardized CO curve using the logarithmic function CO = SR[ln-(PLA - 2.03) + 0.80] for the left heart and CO = SR[ln(PRA - 2.13) + 1.90] for the right heart, where SL and SR represent the preload sensitivity of CO, i.e., pumping ability, of the left and right heart, respectively. To estimate the integrated CO curve in each animal, we calculated SL and SR from single-point CO, PLA, and P RA measurements. Estimated and measured CO agreed reasonably well. In another eight dogs, we altered stressed blood volume (-8 to +8 ml/kg of reference volume) under normal and heart failure conditions and predicted the hemodynamics by intersecting the surface and the CO curve thus estimated. We could predict CO [y = 0.93x + 6.5, r2 = 0.96, standard error of estimate (SEE) = 7.5 ml · min-1·kg-1], PLA (y = 0.90x + 0.5, r2 = 0.93, SEE = 1.4 mmHg), and PRA (y = 0.87x + 0.4, r2 = 0.91, SEE = 0.4 mmHg) reasonably well. In conclusion, single-point estimation of the integrated CO curve enables accurate prediction of hemodynamics in response to extensive changes in stressed blood volume. Copyright © 2005 the American Physiological Society.

DOI： 10.1152/ajpheart.01237.2004

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掲載種別：研究論文（学術雑誌）  

The dynamic characteristics of the baroreflex neural arc from pressure input to efferent sympathetic nerve activity (SNA) reveal derivative characteristics in the frequency range of 0.01 to 0.8 Hz (i.e., the baroreflex gain augments with increasing frequency) and high-cut characteristics in the frequency range above 0.8 Hz (i.e., the baroreflex gain decreases with increasing frequency) in rabbits. The derivative characteristics accelerate the arterial pressure regulation via the baroreflex. The high-cut characteristics preserve the baroreflex gain against pulsatile pressure by attenuating the high-frequency components less necessary for arterial pressure regulation. However, to what extent the carotid sinus baroreceptor transduction from pressure input to afferent baroreceptor nerve activity (BNA) contributes to these characteristics remains unanswered. To test the hypothesis that the carotid sinus pressure-BNA transduction partly explains the derivative characteristics but not the high-cut characteristics, we examined the dynamic BNA response to pressure input in the frequency range from 0.01 to 3 Hz by using a white noise analysis in 7 anesthetized rabbits. The transfer function from pressure input to BNA showed slight derivative characteristics in the frequency range from 0.01 to 0.3 Hz with approximately a 1.7-fold increase in dynamic gain, but it showed no high-cut characteristics. In conclusion, the carotid sinus baroreceptor transduction partly explained the derivative characteristics but not the high-cut characteristics of the baroreflex neural arc. The present results suggest the importance of the central processing from BNA to efferent SNA to account for the overall dynamic characteristics of the baroreflex neural arc.

DOI： 10.2170/jjphysiol.R2122

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掲載種別：研究論文（学術雑誌）  

An intermittent exposure to artificial hypergravity with physical exercise by a human centrifuge may provide a countermeasure against various physiological problems after space flight. To test the effects of hypergravity with ergometric exercise on dynamic regulation of heart rate during weightlessness, we quantified autonomic cardiovascular control before and after head-down-tilt bed rest (HDBR) with and without the countermeasure. Twelve male subjects underwent a 14-day period of HDBR. Six of them were exposed to a hypergravity (+1.2 Gz acceleration at heart level) for 30 min with ergometric exercise (60 W, n = 4; 40 W, n = 2) as a countermeasure on day 1, 2, 3, 5, 7, 9, 11, 12, 13 and 14, during HDBR (CM group). The remaining six were not exposed to a hypergravity exercise during HDBR (control group). Blood pressure and ECG were recorded at a supine position before and after HDBR. The high frequency power of R-R interval (HFRR; 1,008±238 to 353±56 ms2 P < 0.05) as an index of cardiac parasympathetic activity, and transfer function gain between BP and R-R interval in the high frequency range (GainHF; 21.9±5.4 to 14.5±4.2 ms/mmHg, P < 0.01) as an index of vagally mediated arterial-cardiac baroreflex, decreased significantly after HDBR in the control group. However, these changes were not statistically significant in the CM group (HFRR, 1,150±344 to 768±385 ms2; GainHF, 21.5±3.3 to 18.6±3.4 ms/mmHg). Moreover, baroreflex gain by sequence analysis showed similar results. This observation suggests that the intermittent exposure to hypergravity with ergometric exercise may attenuate the decreases in the parasympathetic activity and the spontaneous arterial-cardiac baroreflex function after weightlessness. © Springer-Verlag 2005.

DOI： 10.1007/s00421-004-1308-x

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：BMC  

Background: Due to its easy applicability, pulse wave has been proposed as a surrogate of electrocardiogram (ECG) for the analysis of heart rate variability (HRV). However, its smoother waveform precludes accurate measurement of pulse-to-pulse interval by fiducial-point algorithms. Here we report a pulse frequency demodulation (PFDM) technique as a method for extracting instantaneous pulse rate function directly from pulse wave signal and its usefulness for assessing pulse rate variability (PRV).Methods: Simulated pulse wave signals with known pulse interval functions and actual pulse wave signals obtained from 30 subjects with a trans-dermal pulse wave device were analyzed by PFDM. The results were compared with heart rate and HRV assessed from simultaneously recorded ECG.Results: Analysis of simulated data revealed that the PFDM faithfully demodulates source interval function with preserving the frequency characteristics of the function, even when the intervals fluctuate rapidly over a wide range and when the signals include fluctuations in pulse height and baseline. Analysis of actual data revealed that individual means of low and high frequency components of PRV showed good agreement with those of HRV (intraclass correlation coefficient, 0.997 and 0.981, respectively).Conclusion: The PFDM of pulse wave signal provides a reliable assessment of PRV. Given the popularity of pulse wave equipments, PFDM may open new ways to the studies of long-term assessment of cardiovascular variability and dynamics.

DOI： 10.1186/1475-925X-4-62

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掲載種別：研究論文（学術雑誌）  

A bionic baroreflex system (BBS) is a computer-assisted intelligent feedback system to control arterial pressure (AP) for the treatment of baroreflex failure. To apply this system clinically, an appropriate efferent neural (sympathetic vasomotor) interface has to be explored. We examined whether the spinal cord is a candidate site for such interface. In six anesthetized and baroreflex-deafferentiated cats, a multielectrode catheter was inserted into the epidural space to deliver epidural spinal cord stimulation (ESCS). Stepwise changes in ESCS rate revealed a linear correlation between ESCS rate and AP for ESCS rates of 2 pulses/s and above (r2, 0.876-0.979; slope, 14.3 ± 5.8 mmHg·pulses-1·s; pressure axis intercept, 35.7 ± 25.9 mmHg). Random changes in ESCS rate with a white noise sequence revealed dynamic transfer function of peripheral effectors. The transfer function resembled a second-order, low-pass filter with a lag time (gain, 16.7 ± 8.3 mmHg·pulses-1·s; natural frequency, 0.022 ± 0.007 Hz; damping coefficient, 2.40 ± 1.07; lag time, 1.06 ± 0.41 s). On the basis of the transfer function, we designed an artificial vasomotor center to attenuate hypotension. We evaluated the performance of the BBS against hypotension induced by 60° head-up tilt. In the cats with baroreflex failure, head-up tilt dropped AP by 37 ± 5 mmHg in 5 s and 59 ± 11 mmHg in 30 s. BBS with optimized feedback parameters attenuated hypotension to 21 ± 2 mmHg in 5 s (P < 0.05) and 8 ± 4 mmHg in 30 s (P < 0.05). These results indicate that ESCS-mediated BBS prevents orthostatic hypotension. Because epidural stimulation is a clinically feasible procedure, this BBS can be applied clinically to combat hypotension associated with various pathophysiologies.

DOI： 10.1152/japplphysiol.00162.2004

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掲載種別：研究論文（学術雑誌）  

We studied the effects of 14 days of 6° head-down bed rest (HDBR) in 16 healthy male subjects to examine the functional changes in the autonomic nervous system and cardiac baroreceptor reflex response with an emphasis on dynamic changes during HDBR. Beat-by-beat RR intervals (RRIs) and systolic arterial pressures (SAPs) were measured non-invasively from simultaneous, continuous recordings of ECG and arterial pressure waves in supine resting postures. A power spectrum analysis by the fast Fourier transform was applied to a data set composed of interpolated 512 RRIs and 512 SAPs (256 s in duration). Three indices of cardiac baroreceptor reflex sensitivity (BRS) were obtained by applying a sequence technique and a cross-spectrum analysis technique to the spontaneous RRIs and SAPs. The high-frequency band power of RRI variability (HFRRI) decreased significantly in the latter part of HDBR and persisted until the initial stage of the post-HDBR period (POST). The low-frequency band power of SAP variability decreased significantly only during the mid-part of HDBR. The BRSsequence obtained by the sequence technique showed a significant increase temporarily on the initial day of HDBR. The BRSsequence and the estimate of BRS obtained by the cross-spectrum analysis handling the high-frequency band were both significantly decreased on the initial day of POST. Each of the BRS estimates correlated negatively with heart rate and positively with HFRRI during HDBR and POST. These results suggest the following: (1) cardiac spontaneous baroreceptor reflex sensitivity might be transiently increased at the initial stage of HDBR, (2) the reduction in vagal modulation on the sinus node occurs from the latter part of HDBR to the initial stage of POST, (3) sympathetic vasomotor control is probably slightly inhibited during the mid-part of HDBR, and (4) the enhancement in cardiac sympathetic modulation and the impairment in cardiac spontaneous baroreceptor reflex sensitivity may occur in the initial stage of POST. © Springer-Verlag 2004.

DOI： 10.1007/s00421-004-1067-8

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掲載種別：研究論文（学術雑誌）  

Neuronal uptake is the most important mechanism by which norepinephrine (NE) is removed from the synaptic clefts at sympathetic nerve terminals. We examined the effects of neuronal NE uptake blockade on the dynamic sympathetic regulation of the arterial baroreflex because dynamic characteristics are important for understanding the system behavior in response to exogenous disturbance. We perturbed intracarotid sinus pressure (CSP) according to a binary white noise sequence in anesthetized rabbits, while recording cardiac sympathetic nerve activity (SNA), arterial pressure (AP), and heart rate (HR). Intravenous administration of desipramine (1 mg/kg) decreased the normalized gain of the neural arc transfer function from CSP to SNA relative to untreated control (1.03 ± 0.09 vs. 0.60 ± 0.08 AU/mmHg, mean ± SE, P < 0.01) but did not affect that of the peripheral arc transfer function from SNA to AP (1.10 ± 0.05 vs. 1.08 ± 0.10 mmHg/AU). The normalized gain of the transfer function from SNA to HR was unaffected (1.01 ± 0.04 vs. 1.09 ± 0.12 beats·min-1·AU-1). Desipramine decreased the natural frequency of the transfer function from SNA to AP by 28.7 ± 7.0% (0.046 ± 0.007 vs. 0.031 ± 0.002 Hz, P < 0.05) and that of the transfer function from SNA to HR by 64.4 ± 2.2% (0.071 ± 0.003 vs. 0.025 ± 0.002 Hz, P < 0.01). In conclusion, neuronal NE uptake blockade by intravenous desipramine administration reduced the total buffering capacity of the arterial baroreflex mainly through its action on the neural arc. The differential effects of neuronal NE uptake blockade on the dynamic AP and HR responses to SNA may provide clues for understanding the complex pathophysiology of cardiovascular diseases associated with neuronal NE uptake deficiency.

DOI： 10.1152/ajpregu.00527.2003

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掲載種別：研究論文（学術雑誌）  

A cascade model comprised of a derivative filter followed by a nonlinear sigmoidal component reproduces the input size dependence of transfer gain in the baroreflex neural arc from baroreceptor pressure input to efferent sympathetic nerve activity (SNA). We examined whether the same model could predict the operating point dependence of the baroreflex neural arc transfer characteristics estimated by a binary white noise input. In eight anesthetized rabbits, we isolated bilateral carotid sinuses from the systemic circulation and controlled intracarotid sinus pressure (CSP). We estimated the linear transfer function from CSP to SNA while varying mean CSP among 70, 100, 130, and 160 mmHg (P70, P100, P130, and P 160, respectively). The transfer gain at 0.01 Hz was significantly smaller at P70 (0.61 ± 0.26) and P160 (0.60 ± 0.25) than at Ploo (1.32 ± 0.42) and P130 (1.36 ± 0.45) (in arbitrary units/mmHg; means ± SD; P < 0.05). In contrast, transfer gain values above 0.5 Hz were similar among the protocols. As a result, the slope of increasing gain between 0.1 and 0.5 Hz was significantly steeper at P70 (17.6 ± 3.6) and P160 (14.1 ± 4.3) than at P100 (8.1 ± 4.4) and P 130 (7.4 ± 6.6) (in dB/decade; means ± SD; P < 0.05). These results were consistent with those predicted by the derivative-sigmoidal model, where the deviation of mean input pressure from the center of the sigmoidal nonlinearity reduced the transfer gain mainly in the low-frequency range. The derivative-sigmoidal model functionally reproduces the dynamic SNA regulation by the arterial baroreflex over a wide operating range.

DOI： 10.1152/ajpheart.00787.2003

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掲載種別：研究論文（学術雑誌）  

A novel framework of circulatory equilibrium was developed by extending Guyton's original concept. In this framework, venous return (COV) for a given stressed volume (V) was characterized by a flat surface as a function of right atrial pressure (PRA) and left atrial pressure (PLA) as follows: COV = V/W - GSPRA - GPPLA, where W, GS, and GP denote linear parameters. In seven dogs under total heart bypass, COV, PRA, PLA, and V were varied to determine the three parameters in each animal with use of multivariate analysis. The coefficient of determination (r2 = 0.92-0.99) indicated the flatness of the venous return surface. The averaged surface was COV = V/0.129 - 19.61P RA - 3.49PLA. To examine the invariability of the surface parameters among animals, we predicted the circulatory equilibrium in response to changes in stressed volume in another 12 dogs under normal and heart failure conditions. This was achieved by equating the standard surface with the individually measured cardiac output (CO) curve. In this way, we could predict CO [y = 0.90x + 5.6, r2 = 0.95, standard error of the estimate (SEE) = 8.7 ml·min-1·kg-1], PRA (y = 0.96x, r2 = 0.98, SEE = 0.2 mmHg), and PLA (y = 0.89x + 0.5, r2 = 0.98, SEE = 0.8 mmHg) reasonably well. We conclude that the venous return surface accurately represents the venous return properties of the systemic and pulmonary circulations. The characteristics of the venous return surface are invariable enough among animals, making it possible to predict circulatory equilibrium, even if those characteristics are unknown in individual animals.

DOI： 10.1152/ajpheart.00654.2003

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掲載種別：研究論文（学術雑誌）  

Although spaceflight and bed rest are known to cause muscular atrophy in the antigravity muscles of the legs, the changes in sympathetic and cardiovascular responses to exercises using the atrophied muscles remain unknown. We hypothesized that bed rest would augment sympathetic responses to isometric exercise using antigravity leg muscles in humans. Ten healthy male volunteers were subjected to 14-day 6° head-down bed rest. Before and after bed rest, they performed isometric exercises using leg (plantar flexion) and forearm (handgrip) muscles, followed by 2-min postexercise muscle ischemia (PEMI) that continues to stimulate the muscle metaboreflex. These exercises were sustained to fatigue. We measured muscle sympathetic nerve activity (MSNA) in the contralateral resting leg by microneurography. In both pre- and post-bed-rest exercise tests, exercise intensities were set at 30 and 70% of the maximum voluntary force measured before bed rest. Bed rest attenuated the increase in MSNA in response to fatiguing plantar flexion by ∼70% at both exercise intensities (both P < 0.05 vs. before bed rest) and reduced the maximal voluntary force of plantar flexion by 15%. In contrast, bed rest did not alter the increase in MSNA response to fatiguing handgrip and had no effects on the maximal voluntary force of handgrip. Although PEMI sustained MSNA activation before bed rest in all trials, bed rest entirely eliminated the PEMI-induced increase in MSNA in leg exercises but partially attenuated it in forearm exercises. These results do not support our hypothesis but indicate that bed rest causes a reduction in isometric exercise-induced sympathetic activation in (probably atrophied) antigravity leg muscles.

DOI： 10.1152/ajpregu.00497.2003

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掲載種別：研究論文（学術雑誌）  

A 14-day, 6° head-down bed rest (HDBR) study was conducted with 12 healthy young men to determine whether there are transient responses of the cardiovascular autonomic regulatory system including cardiovascular, autonomic nervous, and cardiac baroreceptor reflex functions in the acute phases of HDBR and post-HDBR. Compared with the supine position before bed rest, the high-frequency band power (HFRRI) of RR intervals (RRIs) decreased significantly at 3, 6, and 24 h of HDBR. This tendency went on until 24 h post-HDBR. Three kinds of cardiac baroreceptor reflex sensitivity (BRS) were estimated from closed-loop approaches to simultaneously recorded spontaneous RRI and systolic arterial pressure (SAP) fluctuations. BRSsequence is based on the simultaneous changes between RRI and SAP. αLF and αHF are based on a cross-spectrum analysis for low- and high-frequency bands of RRI and SAP. Although BRSsequence decreased significantly at acute phases of both HDBR and post-HDBR, neither αLF nor αHF decreased significantly at any of the acute phases of HDBR and post-HDBR. Our results suggest that HF RRI and BRSsequence can be used effectively to reveal reductions in cardiac vagal nervous modulation on the sinus node and cardiac BRS within 24 h of both HDBR and post-HDBR. © 2004 Elsevier B.V. All rights reserved.

DOI： 10.1016/j.autneu.2004.01.001

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掲載種別：研究論文（学術雑誌）  

We investigated the effect of head-down bed rest (HDBR) for 14 days on thermoregulatory sweating and cutaneous vasodilation in humans. Fluid intake was ad libitum during HDBR. We induced whole body heating by increasing skin temperature for 1 h with a water-perfused blanket through which hot water (42°C) was circulated. The experimental room was air-conditioned (27°C, 30-40% relative humidity). We measured skin blood flow (chest and forearm), skin temperatures (chest, upper arm, forearm, thigh, and calf), and tympanic temperature. We also measured sweat rate by the ventilated capsule method in which the skin area for measurement was drained by dry air conditioned at 27°C under similar skin temperatures in both trials. We calculated cutaneous vascular conductance (CVC) from the ratio of skin blood flow to mean blood pressure. From tympanic temperature-sweat rate and -CVC relationships, we assessed the threshold temperature and sensitivity as the slope response of variables to a given change in tympanic temperature. HDBR increased the threshold temperature for sweating by 0.31°C at the chest and 0.32°C at the forearm, whereas it reduced sensitivity by 40% at the chest and 31% at the forearm. HDBR increased the threshold temperature for cutaneous vasodilation, whereas it decreased sensitivity. HDBR reduced plasma volume by 11%, whereas it did not change plasma osmolarity. The increase in the threshold temperature for sweating correlated with that for cutaneous vasodilation. In conclusion, HDBR attenuated thermoregulatory sweating and cutaneous vasodilation by increasing the threshold temperature and decreasing sensitivity. HDBR increased the threshold temperature for sweating and cutaneous vasodilation by similar magnitudes, whereas it decreased their sensitivity by different magnitudes.

DOI： 10.1152/japplphysiol.00025.2003

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掲載種別：研究論文（学術雑誌）  

Spaceflight and its ground-based simulation model, 6° head-down bed rest (HDBR), cause cardiovascular deconditioning in humans. Because sympathetic vasoconstriction plays a very important role in circulation, we examined whether HDBR impairs α-adrenergic vascular responsiveness to sympathetic nerve activity. We subjected eight healthy volunteers to 14 days of HDBR and before and after HDBR measured calf muscle sympathetic nerve activity (MSNA; microneurography) and calf blood flow (venous occlusion plethysmography) during sympathoexcitatory stimulation (rhythmic handgrip exercise). HDBR did not change the increase in total MSNA (P = 0.97) or the decrease in calf vascular conductance (P = 0.32) during exercise, but it did augment the increase in calf vascular resistance (P = 0.0011). HDBR augmented the transduction gain from total MSNA into calf vascular resistance, assessed as the least squares linear regression slope of vascular resistance on total MSNA (0.05 ± 0.02 before HDBR, 0.20 ± 0.06 U·min-1·burst -1 after HDBR, P = 0.0075), but did not change the transduction gain into calf vascular conductance (P = 0.41). Our data indicate that α-adrenergic vascular responsiveness to sympathetic nerve activity is preserved in the supine position after HDBR in humans.

DOI： 10.1152/ajpregu.00685.2002

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掲載種別：研究論文（国際会議プロシーディングス）  

To test the effectiveness of centrifuge-induced artificial gravity with ergometric exercise, 12 healthy young men (20.7 ±1.9 yrs) were exposed to simulated microgravity for 14 days of -6° head-down bedrest. Half the subjects were randomly selected and loaded 1.2 G artificial gravity with 60 W (four out of six subjects) or 40 W (two out of six subjects) of ergometric workload on days 1, 2, 3, 5, 7, 9, 11. 12, 13, 14 (CM group). The rest of the subjects served as the control. Anti-G score, defined as the G-load × running time to the endpoint, was significantly elongated by the load of the centrifuge-ergometer. Plasma volume loss was suppressed (-5.0 ± 2.4 vs -16.4 ± 1.9 %), and fluid volume shift was prevented by the countermeasure load. Elevated heart rate and muscle sympathetic nerve activity after bedrest were counteracted, and exaggerated response to head-up tilt was also suppressed. Centrifuge-induced artificial gravity with exercise is effective in preventing cardiovascular deconditioning due to microgravity exposure, however, an effective and appropriate regimen (magnitude of G-load and exercise workload) should be determined in future studies.

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掲載種別：研究論文（学術雑誌）  

The effects of the muscle mechanoreflex on the arterial baroreflex neural control have not previously been analyzed over the entire operating range of the arterial baroreflex. In anesthetized, vagotomized, and aortic-denervated rabbits (n = 8), we isolated carotid sinuses and changed intracarotid sinus pressure (CSP) from 40 to 160 mmHg in increments of 20 mmHg every minute while recording renal sympathetic nerve activity (SNA) and arterial pressure (AP). Muscle mechanoreflex was induced by passive muscle stretch (5 kg of tension) of the hindlimb. Muscle stretch shifted the CSP-SNA relationship (neural arc) to a higher SNA, whereas it did not affect the SNA-AP relationship (peripheral arc). SNA was almost doubled [from 63 ± 15 to 118 ± 14 arbitrary units (au), P < 0.05] at the CSP level of 93 ± 8 mmHg, and AP was increased ∼50% by muscle stretch. When the baroreflex negative feedback loop was closed, muscle stretch increased SNA from 63 ± 15 to 81 ± 21 au (P < 0.05) and AP from 93 ± 8 to 109 ± 12 mmHg (P < 0.05). In conclusion, the muscle mechanoreflex resets the neural arc to a higher SNA, which moves the operating point towards a higher SNA and AP under baroreflex closed-loop conditions. Analysis of the baroreflex equilibrium diagram indicated that changes in the neural arc induced by the muscle mechanoreflex might compensate for pressure falls resulting from exercise-induced vasodilatation.

DOI： 10.1152/ajpheart.00801.2003

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掲載種別：研究論文（学術雑誌）  

Although orthostatic hypotension is a common clinical syndrome after spaceflight and its ground-based simulation model, 6° head-down bed rest (HDBR), the pathophysiology remains unclear. The authors' hypothesis that a decrease in sympathetic nerve activity is the major pathophysiology underlying orthostatic hypotension after HDBR was tested in a study involving 14-day HDBR in 22 healthy subjects who showed no orthostatic hypotension during 15-min 60° head-up tilt test (HUT) at baseline. After HDBR, 10 of 22 subjects demonstrated orthostatic hypotension during 60° HUT. In subjects with orthostatic hypotension, total activity of muscle sympathetic nerve activity (MSNA) increased less during the first minute of 60° HUT after HDBR (314% of resting supine activity) than before HDBR (523% of resting supine activity, P < 0.05) despite HDBR-induced reduction in plasma volume (13% of plasma volume before HDBR). The postural increase in total MSNA continued during several more minutes of 60° HUT while arterial pressure was maintained. Thereafter, however, total MSNA was paradoxically suppressed by 104% of the resting supine level at the last minute of HUT (P < 0.05 vs. earlier 60° HUT periods). The suppression of total MSNA was accompanied by a 22 ± 4-mmHg decrease in mean blood pressure (systolic blood pressure <80 mmHg). In contrast, orthostatic activation of total MSNA was preserved throughout 60° HUT in subjects who did not develop orthostatic hypotension. These data support the hypothesis that a decrease in sympathetic nerve activity is the major pathophysiological factor underlying orthostatic hypotension after HDBR. It appears that the diminished sympathetic activity, in combination with other factors associated with HDBR (e.g., hypovolemia), may predispose some individuals to postural hypotension.

DOI： 10.1152/ajpheart.00965.2002

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掲載種別：研究論文（学術雑誌）  

Since human thermoregulatory heat loss responses, cutaneous vasodilation and sweating, cause hypovolemia, they should resultantly stimulate human baroreflexes. However, it is possible that the thermoregulatory system directly interacts with the baroreflex system through central neural connections independently of the heat-induced hypovolemia. We hypothesized that heat stress modifies the baroreflex control of sympathetic nerve activity independently of heat-induced hypovolemia in humans. We made whole-body heating with tubelined suits perfused with warm water (46-47°C) on 10 healthy male subjects. The heating increased skin and tympanic temperatures by 10.0 and 0.4°C, respectively. It increased resting total muscle sympathetic nerve activity (MSNA, microneurography) by 94±9% and decreased central venous pressure (CVP, dependent arm technique) by 2.6±0.9 mmHg. The heating increased arterial baroreflex gain by 193%, assessed as a response of MSNA to a decrease in diastolic arterial pressure during Valsalva's maneuver, but it did not change threshold arterial pressure for MSNA activation. Although the heating did not change the cardiopulmonary baroreflex gain assessed as a response of MSNA to a change in estimated central venous pressure (CVP) during a 10° head-down and -up tilt test, it upwardly shifted the stimulus-response baroreflex relationship. These changes in baroreflex functions during heating were not restored by an intravenous infusion of warmed isotonic saline (37°C, 15 ml/kg) that restored the heat-induced reduction of CVP. Our results support our hypothesis that heat stress modifies the baroreflex control of MSNA independently of heat-induced hypovolemia in humans. Our results also suggest that the hyperthermal modification of baroreflex results from central neural interaction between thermoregulatory and baroreflex systems.

DOI： 10.2170/jjphysiol.53.215

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掲載種別：研究論文（学術雑誌）  

Although angina pectoris in patients with coronary heart disease often occurs when their forearms are in an elevated position for a prolonged period, and sympathetic activation is a major cause of this condition, little is known about the physiological effects of forearm elevation on sympathetic activity during forearm exercise. We hypothesized that forearm elevation augments sympathetic activation during the static handgrip exercise in humans. A total of 10 healthy male volunteers performed 2 min of static handgrip exercise at 30% of maximal voluntary contraction followed by 2 min of post-exercise muscle ischaemia (PEMI; specific activation of the muscle metaboreflex) with two forearm positions: the exercising forearm was elevated 50 cm above the heart (forearm-elevated trial) or fixed at the level of the heart (heart-level trial). Muscle sympathetic nerve activity (MSNA), blood pressure and heart rate were monitored. MSNA increased during handgrip exercise in both forearm positions (P < 0.001); the increase was 51% greater in the forearm-elevated trial (516±99 arbitrary units) than in the heart-level trial (346±44 units; P < 0.05). The increase in mean blood pressure was 8.4 mmHg greater during exercise in the forearm-elevated trial (P < 0.05), while changes in heart rate were similar in both forearm positions. The increase in MSNA during PEMI was 71% greater in the forearm-elevated trial (393±71 arbitrary units/min) than in the heart-level trial (229±29 units/min; P < 0.05). These results support the hypothesis that forearm elevation augments sympathetic activation during handgrip exercise. The excitatory effect of forearm elevation on exercising MSNA may be mediated primarily by increased activation of the muscle metaboreflex.

DOI： 10.1042/cs1030295

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掲載種別：研究論文（学術雑誌）  

The strength of sympathetic vasoconstrictor nerve traffic to the skin has an important role in human thermoregulation since it controls heat loss from the skin by constricting or dilating cutaneous blood vessels. This study sought to clarify the time relationship between a reduction of the vasoconstrictor activity induced by elevating the ambient temperature (Ta), and subsequent change of core temperature (Tty). For this purpose, we recorded peroneal skin sympathetic nerve activity (SSNA), laser Doppler skin blood flow, skin and core (tympanic) temperatures in 11 subjects while increasing Ta from 15 to 30°C during ∼30 min. We observed a significant suppression of SSNA 7.7 min after Ta rise with marked interindividual variations. Tty displayed an increase with a peak after 8.2 min followed by a successive decrease, which became significant 14 min after the Ta rise. The rate of decrease of vasoconstrictor SSNA correlated both with the rate of decrease of Tty (P<0.01) and the magnitude of the Tty decrease (P<0.0005). A cross-correlogram between SSNA and Tty showed a peak at 7 min (r=0.52). We conclude that a Ta rise-induced reduction of skin vasoconstrictor nerve traffic leads to a core temperature decrease after 7-8 min. © 2002 Elsevier Science Ireland Ltd. All rights reserved.

DOI： 10.1016/S0304-3940(02)00374-9

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掲載種別：研究論文（学術雑誌）  

This study aimed at examining whether the properties of microneurographically recorded muscle sympathetic nerve activity (MSNA) were altered during hypotensive attacks. A retrospective study was performed on 74 subjects who participated in tilt studies when vasodepressive syncope was induced incidentally in six subjects. The specific features of MSNA that distinguish this activity from skin sympathetic nerve activity are (1) rhythmic pulse synchronous burst discharge, (2) a duration of approximately 150-300 ms, and (3) no response to arousal stimuli were abolished during the syncopal attack. The altered features observed during the syncopal attack in these six subjects were (1) scattered reflex latencies of MSNA peak from the ECG R-wave, (2) elongated burst duration twice to five times as long as that in conscious state, and (3) response to arousal stimuli. The reduced input from the baroreceptors due to suppression on the central sympathetic volley proximal to the nucleus tractus solitarius might be attributed to the lost features characteristic of MSNA. Copyright © 2002 Elsevier Science B.V.

DOI： 10.1016/S1566-0702(01)00362-9

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掲載種別：研究論文（学術雑誌）  

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掲載種別：研究論文（学術雑誌）  

To test the hypothesis that leg vein filling and emptying functions could be impaired with advancing age, which would produce less blood volume redistribution toward the lower body and smaller sympathetic reflex response during mild gravitational stress, 9 young and 10 elderly healthy males were exposed to a lower body negative pressure (LBNP) of 15 mmHg. Venous occlusion plethysmography was used to determine the functions of the leg veins. We found that the baseline venous distensibility index (VDI) was lower (0.057±0.004 vs. 0.048± 0.003 ml·100 ml-1·mmHg-1, young vs. elderly; p<0.05), and half-emptying time (T1/2) was shorter (1.6±0.1 vs. 1.3±0.1 s, young vs. elderly; p<0.05) in the elderly. At 15 mmHg-LBNP, VDI was decreased and T1/2 was shortened significantly in the vounq qroup, but only slightly in the elderly group. Neither blood pressure nor heart rate changed significantly in either group. The reduction in peripheral venous pressure, which was recorded from the left antecubital vein at the cubital fossa, was less in the elderly, indicating a smaller decrease in central blood volume during LBNP; however, the enhancement of muscle sympathetic nerve activity was nearly the same as that in the young. We conclude that leg vein filling and emptying functions are impaired in elderly people, producing less blood pooling in the legs and smaller reduction in peripheral venous pressure during LBNP; the maintained sympathetic reflex response might be attributable to the well-preserved baroreflex function control of sympathetic outflow to the muscle in the elderly.

DOI： 10.2170/jjphysiol.52.77

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掲載種別：研究論文（学術雑誌）  

The present study was performed to test the hypothesis that calf venous capacitance would be reduced by mild gravitational stress through a vasomotor reflex in humans, and this response could be diminished with advancing age. Nine young (31±1 years, mean±SE) and 9 elderly (69±1 years) healthy males were exposed to a lower body negative pressure (LBNP) of 15 mmHg. Venous occlusion plethysmography was used to measure calf venous capacitance and calf blood flow. Muscle sympathetic nerve activity (MSNA) was recorded microneurographically from the tibial nerve along with cardiovascular variables. It was found that baseline MSNA was higher [21±4 (mean±SE) vs. 37±5 bursts· min-1, young vs. elderly; p<0.05] and calf venous capacitance was lower (1.71±0.12 vs. 1.44±0.10, ml·100ml-1, young vs. elderly; p< 0.05) in the elderly group. At 15mmHg-LBNP, heart rate and mean arterial pressure both remained unchanged, MSNA was enhanced, and calf blood flow was reduced in all subjects. Calf venous capacitance during LBNP decreased in the young, but did not change in the elderly. A significant negative correlation between percent changes in MSNA and percent changes in calf venous capacitance existed in the young group (y=-0.171x-11.863, r=-0.682; p=0.0432), but disappeared in the elderly group. The ratio of percent changes in calf venous capacitance to percent changes in MSNA was markedly lower in the elderly (p<0.01). In conclusion, these results substantiate our hypothesis that calf venous capacitance is reduced by mild LBNP through the vasomotor reflex, and this response is diminished in the elderly.

DOI： 10.2170/jjphysiol.52.69

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掲載種別：研究論文（学術雑誌）  

Responses of Hoffman-reflex in the soleus muscle to changes of gravity levels created by parabolic flight of a jet airplane were investigated in four healthy male subjects. The subjects maintained a sitting position with seat belts fastened, keeping the anterior ankle and posterior knee angles at ∼135°. The gravity levels were altered from 1- to 2-G, and then microgravity was created for ∼20 s. The levels were recovered from 1.5- to 1-G during the descending phase. The time interval between the stimulation and either M- or H-wave was not influenced by the changes in gravity levels. The amplitude of the M-wave during hyper- and microgravity was identical to that obtained at 1-G. However, the H-wave amplitude was increased when the subjects were exposed to microgravity (∼four times vs. 1-G level). The H/M ratio was also elevated during microgravity. Further, such a phenomenon was maintained throughout the 20 s of microgravity exposure. Hypergravity at 1.5- or 2-G had no effect on the H-wave amplitude. It is suggested that an acute exposure to microgravity increases the excitability of the soleus motor pool and the increased excitability is restored immediately when the gravity level is elevated. © 2001 Elsevier Science Ltd. All rights reserved.

DOI： 10.1016/S0304-3940(01)02367-9

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掲載種別：研究論文（学術雑誌）  

The purpose of the present study was to investigate the alterations in thermoregulatory control following 14 days of head-down bed rest (HDBR). The threshold temperature for sweating onset and sweating sensitivity were determined from sweating rates on the chest and forearm, and tympanic temperature as an index of core temperature (Tc) in nine healthy males exposed to a 60-min heat stress with a water-perfused blanket before and after HDBR. The threshold temperature for sweating onset, that is, the Tc at which sweating began on the chest and forearm was 36.75 +/- 0.14 and 36.72 +/- 0.13 degrees C before HDBR, respectively. The value significantly increased to 37.05 +/- 0.09 (p<0.05) for the chest and 37.04 +/- 0.08 degrees C (p<0.05) for the forearm after HDBR. On the other hand, the sweating sensitivity which was indicated as a slope of the Tc-sweating rate relationship significantly decreased from 4.20 +/- 1.15 to 2.32 +/- 1.18 for the chest (p<0.05) and from 4.20 +/- 1.06 to 2.92 +/- 0.98 mg/min/cm2/degrees C for the forearm (p<0.05) after HDBR. These findings suggest that the heat-dissipatory function was attenuated after 14 days of HDBR.

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掲載種別：研究論文（学術雑誌）  

To clarify the response of muscle sympathetic nerve activity (MSNA) to static stimulation of otolith organs in a craniocaudal direction (+Gz) in humans, we examined the effect of otolith stimulation on MSNA without changing the effect of cardiopulmonary baroreceptors using a 6-8.5 degrees head-down tilt (HDT) and lower body negative pressure (LBNP) device. Before the study, we established that 6-8.5 degrees HDT with 10 mmHg LBNP caused a fluid shift to the degree that the thoracic impedance was the same as the supine position without LBNP. Subjects were young male volunteers aged 22.1 +/- 3.8 years who gave informed consent. MSNA was recorded from the tibial nerve by microneurography simultaneously with heart rate (ECG), thoracic fluid volume (impedance method), and blood pressure (tonometric method). During 6-8.5 degrees HDT with 10 mmHg LBNP, MSNA was suppressed slightly without significantly changing heart rate, thoracic impedance, or mean arterial blood pressure. The results suggest that the sympathosuppression was related not to the result of cardiopulmonary [correction of cardioplumonary] loading but to the -Gz change (caudocranial direction [correction of dirction]) of 0.1 G. It is estimated that the vestibulo-sympathetic reflex may suppress sympathetic outflow to muscles in humans.

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掲載種別：研究論文（学術雑誌）  

The purpose of the present study was to clarify how skin sympathetic nerve activity (SSNA) influences the core temperature during local heating of the unilateral sole of the foot for 60 min. We recorded SSNA microneurographically from the tibial or peroneal nerve simultaneously with skin blood flow, sweat rate at heated and non-heated sites, with tympanic temperature (Tty) as the core temperature. Sole heating began to suppress vasoconstrictive SSNA (vasoconstrictor) after 3.4±1.1 min, decrease Tty after 7.4±2.0 min, activate vasoconstrictor after 33.4±2.2 min, and increase Tty after 45.5±2.7 min. Regarding the interaction between vasoconstrictor and Tty during sole heating, we found the following: (1) the capability to suppress vasoconstrictors (decrease rate) showed positive correlations with the time delay from vasoconstrictor suppression to the Tty decrease (r=0.752, p<0.05), and with the Tty decrease rate (r=0.795, p<0.05), (2) the Tty decrease rate was inversely related to the capability to activate vasoconstrictors (increase rate) (r=-0.836, p<0.05), and (3) the capability to activate vasoconstrictors was inversely related to the time delay from vasoconstrictor activation to the Tty increase (r=-0.856, p<0.05) and showed a positive correlation with the Tty increase rate (r=0.819, p<0.05). These significant correlations indicate that the capability to control vasoconstrictors to the skin is one of the determinant factors maintaining core temperature in human thermoregulatory function. In conclusion, human thermoregulatory function is largely dependent on the suppression and activation capability of vasoconstrictors. Copyright © 2001 Elsevier Science B.V.

DOI： 10.1016/S1566-0702(01)00286-7

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掲載種別：研究論文（学術雑誌）  

The benefits of lower body positive pressure (LBPP) are generally accepted for clinical treatment in medical emergencies caused by massive bleeding to maintain the systemic blood pressure. They are also used by NASA post spaceflight for preventing orthostatic hypotension in the astronauts. However, controversy still exists concerning the mechanisms underlying LBPP benefits. The purpose of this study was to test the hypothesis that the baroreflex-mediated enhancement in sympathetic activity would be attenuated by LBPP during an orthostatic challenge in humans. Specifically, we studied 1) the sympathetic activity responses by the microneurographic technique, using direct intraneural measurement of muscle sympathetic nerve activity (MSNA); and 2) the contributions of preload and afterload to the chances in MSNA response during orthostasis on application of LBPP. To accomplish these issues, MSNA was recorded microneurographically along with noninvasive measurement of the cardiovascular variables in all the subjects during exposure to a 70 degrees HUT with 30-mm Hg LBPP.

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掲載種別：研究論文（学術雑誌）  

To clarify if sympathetic outflow is altered in Buerger's disease (thromboangitis obliterans, TAO), we measured skin sympathetic nerve activity (SSNA) in TAO patients, and observed the sweating and vasoconstrictive responses during resting and with activating maneuvers. Multiunit postganglionic sympathetic activity was recorded in a skin fascicle of the tibial nerve innervating the skin of the sole (glabrous skin) and peroneal nerve innervating the skin of the dorsum pedis (hairy skin) from five TAO patients and five healthy subjects simultaneously with skin blood flow and sweat expulsion. TAO patients showed significantly less vasoconstrictor SSNA than healthy subjects (17.0±1.9 vs. 31.5±5.8 bursts/min, P<0.001). Moreover, we found no relationship between vasoconstrictor SSNA and skin blood flow in some patients, while they were well correlated in healthy subjects. There was no evidence for increased sympathetic activity in TAO patients, and no hypersensitive relationship was found between SSNA and skin blood flow. These observations suggested that these TAO patients exhibiting no relationship between skin blood flow reduction and vasoconstrictor activity might not respond to sympathectomy, which is generally expected to result in an increase in skin blood flow. The absence of increased sympathetic nerve activity provides further indirect evidence of a local vascular abnormality in TAO. Copyright © 2001 Elsevier Science B.V.

DOI： 10.1016/S1566-0702(00)00272-1

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掲載種別：研究論文（学術雑誌）  

The present study was performed to test the hypothesis that application of lower body positive pressure (LBPP) during orthostasis would reduce the baroreflex-mediated enhancement in sympathetic activity in humans. Eight healthy young men were exposed to a 70° head-up tilt (HUT) on application of 30 mmHg LBPP. Muscle sympathetic nerve activity (MSNA) was microneurographically recorded from the tibial nerve, along with hemodynamic variables. We found that in the supine position with LBPP, MSNA remained unchanged (13.4 ± 3.3 vs. 11.8 ± 2.3 bursts/min, without vs. with LBPP; P > 0.05), mean arterial pressure was elevated, but arterial pulse pressure and heart rate did not alter. At 70° HUT with LBPP, the enhanced MSNA response was reduced (33.8 ± 5.0 vs. 22.5 ± 2.2 bursts/min, without vs. with LBPP; P < 0.05), mean arterial pressure was higher, the decreased pulse pressure was restored, and the increased heart rate was attenuated. We conclude that the baroreflex-mediated enhancement in sympathetic activity during HUT was reduced by LBPP. Application of LBPP in HUT induced an obvious cephalad fluid shift as well as a restoration of arterial pulse pressure, which reduced the inhibition of the baroreceptors. However, the activation of the intramuscular mechanoreflexes produced by 30 mmHg LBPP might counteract the effects of baroreflexes.

DOI： 10.1152/ajpregu.2001.281.3.r778

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掲載種別：研究論文（学術雑誌）  

To examine effects of static exercise on the arterial baroreflex control of vascular sympathetic nerve activity, 22 healthy male volunteers performed 2 min of static handgrip exercise at 30% of maximal voluntary force, followed by postexercise circulatory arrest (PE-CA). Microneurographic recording of muscle sympathetic nerve activity (MSNA) was made with simultaneous recording of arterial pressure (Portapres). The relationship between MSNA and diastolic arterial pressure was calculated for each condition and was defined as the arterial baroreflex function. There was a close relationship between MSNA and diastolic arterial pressure in each subject at rest and during static exercise and PE-CA. The slope of the relationship significantly increased by >300% during static exercise (P < 0.001), and the x-axis intercept (diastolic arterial pressure level) increased by 13 mmHg during exercise (P < 0.001). These alterations in the baroreflex relationship were completely maintained during PE-CA. It is concluded that static hand-grip exercise is associated with a resetting of the operating range and an increase in the reflex gain of the arterial barorelex control of MSNA.

DOI： 10.1152/ajpregu.2001.281.4.r1134

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掲載種別：研究論文（学術雑誌）  

To elucidate the effect of aging on blood pressure regulation, especially cardiopulmonary baroreflex in humans, we measured the resting value of muscle sympathetic nerve activity (MSNA), heart rate (HR), blood pressure (BP), peripheral venous pressure (PVP), and calf blood flow (CBF) in eight healthy young male subjects and eight healthy aged subjects, and compared the responses to the low level of lower body negative pressure (LBNP) between the two groups. The resting MSNA was higher, and the response of MSNA to LBNP was lower in the aged group than in the young group; the response of PVP to LBNP was also lower in the aged than in the young group. Delta MSNA/delta PVP showed no significant differences between the two groups. The present findings indicate that the effect of LBNP on cardiopulmonary baroreflex is greater in young people than in aged people, but that cardiopulmonary baroreflex may be preserved with advancing age.

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掲載種別：研究論文（学術雑誌）  

The purpose of the present study was to evaluate the effect of hypoperfusion to the static-exercised-muscle induced by arm elevation on muscle sympathetic nerve activity (MSNA) recorded from the right tibial nerve (n= 10) by microneurography. Subjects performed static handgrip exercises (SHG) at 30% of maximal voluntary contraction (MVC) for 2 min, followed by 2 min of posthandgrip muscle ischemia (PHGMI) at the heart level (control) and with the arm elevated (50 cm above heart level). Basal heart rate, mean blood pressure and MSNA responses expressed as burst rate (bursts/min) and total MSNA (%) were unaffected by the arm-position. Heart rate response during SHG was not influenced by the arm elevation, while mean blood pressure and MSNA responses were increased by it (P<0.05). MSNA responses were increased during the second minute of the SHG period (P<0.05) and the PHGMI period (P<0.05) in the elevated arm position. In conclusion, arm elevation increased MSNA responses to SHG and PHGMI, suggesting an increased magnitude of muscle metaboreflex.

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掲載種別：研究論文（学術雑誌）  

Muscle sympathetic nerve activity (MSNA) is activated during mild-intensity isometric handgrip exercise, but not during isometric leg exercise at a similarly relative intensity. It is unclear whether MSNA is increased by leg exercise at heavy intensity in humans. We aimed to examine how MSNA responds to high-intensity, isometric leg exercise in humans. Eight young healthy male volunteers performed isometric plantar flexions of high intensity (70% of MVC) for 2 min, followed by 2 min of post-exercise muscle ischemia (PEMI; isolated muscle metaboreflex stimulation), with monitoring of muscle sympathetic nerve activity (MSNA), heart rate and arterial blood pressure. MSNA was increased at the onset of exercise (p<0.05), and further increased to 512 +/- 111% of baseline at the second min of exercise (p<0.05). Furthermore, MSNA remained elevated above baseline during PEMI (259 +/- 41 % of baseline, p<0.05). Heart rate also rose at the onset of the test (P<0.05) and gradually increased all through the test (p<0.05), but decreased to baseline level during PEMI. Mean blood pressure was progressively increased from the onset to the end of test (p<0.05), and remained elevated above baseline during PEMI (p<0.05). In summary, MSNA was increased progressively throughout high-intensity, isometric plantar flexion in humans, primarily due to muscle metaboreflex.

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掲載種別：研究論文（学術雑誌）  

To test the hypothesis that increased leg venous compliance (LVC) is one of the contributory factors to orthostatic intolerance (OI) after simulated microgravity, 28 healthy young males were exposed to a 14-day head-down bed rest, and LVC was measured by venous occlusion plethysmography. Orthostatic tolerance was evaluated by a 60 degree head-up tilt (HUT) for 15 min. Sixteen subjects suffered from OI after the bed rest. They were then divided into orthostatic tolerance (non-fainters, n=12) and intolerance (fainters, n=16) groups. We found that fainters had significantly larger LVC before bed rest (0.055 +/- 0.003 vs. 0.065 +/- 0.002 ml 100 ml-1 mm Hg-1, non-fainter vs. fainter; P < 0.05). After bed rest, LVC markedly increased in both groups. In all the subjects calf circumference was reduced on average by 4.7% and the percent change in LVC was negatively correlated with the percent change in calf circumference when all subjects' data were combined after bed rest (r = -0.42, P < 0.05). Our results did not support the hypothesis that increased LVC is the contributory factor to OI after a 14-day bed rest; however, the mechanisms behind the large LVC in the fainters before bed rest are unclear, and the initial LVC might be a predictive indicator for OI after microgravity exposure.

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掲載種別：研究論文（学術雑誌）  

To clarify the effects of prostaglandin E1 (PGE1) on the vasoconstrictive responses, we compared the correlation between the amplitude of integrated skin sympathetic nerve activity (SSNA) and per cent reduction in skin blood flow (SBF) before and after the infusion of lipo PGE1 and placebo (bolus one-shot infusion, single blind study), and constant rate infusion of PGE1 (10 and 50 ng kg-1 min-1 by infusion pump, dose- dependency study) in ten healthy men. SSNA was recorded microneurographically from the median nerve simultaneously with SBF by laser Doppler flowmetry at the index fingertip. The measurement was conducted 30 min after injection of lipo PGE1 or placebo, and during the drip infusion of 10 and 50 ng kg-1 min-1 of PGE1 with maneuvers to enhance SSNA. The resting and activated skin blood flow were not significantly different between 10 ng lipo PGE1 and placebo administration, and between baseline and 10, 50 ng kg-1 min-1 of PGE1 injection. The vascular response, defined as the slope of regression line between logarithm of amplitude of integrated SSNA bursts and the reduction in SBF, was significantly suppressed by injection of lipo PGE1 as compared with that by placebo. It was also decreased dose-dependently by the constant rate infusion of PGE1 (10 and 50 ng kg-1 min-1). We concluded that the intravenous injection of PGE1 attenuates vasoconstrictive responses to SSNA, and analysis of the relations between SSNA and vasoconstrictive response, i.e. the neuroeffector response, is suggested to be an important tool to assess the drug effect. (C) 2000 Elsevier Science Ireland Ltd.

DOI： 10.1016/S0304-3940(00)01463-4

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掲載種別：研究論文（学術雑誌）  

The purpose of the present study is to examine the changes in the arterial baroreflex control of muscle sympathetic nerve activity (MSNA) after head-down bed rest (HDBR), in relation to orthostatic hypotension after HDBR. Therefore, we performed 60 degrees head-up tilt (HUT) tests before and after 14 days of HDBR, with monitoring MSNA, heart rate and blood pressure. We calculated the gain of the arterial baroreflex control of MSNA, and compared the gains between the subjects who did (defined as the fainters) and those who did not (defined as the nonfainters) become presyncopal in HUT tests after HDBR.

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掲載種別：研究論文（学術雑誌）  

The purpose of this paper is to report our recent investigations on the relationship between sympathetic tone and leg venous compliance, as well as on the baroreflex control of leg venous compliance after simulated microgravity exposure in healthy humans.

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掲載種別：研究論文（学術雑誌）  

Exposure to microgravity or simulated microgravity is known to affect regulatory function in autonomic nervous system. With regard to thermoregulation, simulated microgravity impairs sweating and induces lower skin and higher internal temperatures during physical work. During supine rest after HDT bed rest, the internal temperatures were reported to be higher than those of pre-HDT bed rest in some studies but not in others. There is no report about the dynamic changes of skin blood flow during 14-day HDT bed rest. The process of HDT bed-rest deconditioning on the function of the thermoregulatory system is virtually unknown. The HDT induces an immediate cephalad fluid shift which would inhibit the sympathetic outflow through the arterial and cardiopulmonary baroreflexes, which may increase the skin blood flow. On the other hand, prolonged HDT bed rest induces dehydration, which will increase sympathetic outflow through cardiopulmonary baroreceptor modulation. Both sympathetic activation and dehydration itself will decrease skin blood flow. It seems probable that the general effect on skin blood flow may reverse along the HDT bed rest. However, the dynamic characters of skin blood flow and body temperature during the HDT bed rest have not been studied thoroughly. Therefore, the purpose of present study was to investigate the changes of skin blood flow and body temperature during 14 days HDT bed rest.

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掲載種別：研究論文（学術雑誌）  

Decrease in muscle perfusion affects on cardiovascular response to exercise. Muscle hypoperfusion enhances the increase in blood pressure responses to exercise. Muscle perfusion depends not only on central blood pressure but also how fit the active muscle is above or below the heart level; muscle perfusion decreases as arm is elevated. Static exercise increases muscle sympathetic nerve activity (MSNA) innervating vessels in non-active muscles. The exercise-induced increase in MSNA is mainly mediated by stimulating chemosensitive muscle afferents in active muscles. However, the effect of arm elevation on MSNA during forearm exercise is not examined. On the other hand, space flight and simulated microgravity exposure causes reduction in muscle blood flow, suggesting chronic muscle hypoperfused condition during simulated microgravity. Therefore, there is a possibility that arm elevation after microgravity exposure alters MSNA responsiveness during exercise. However, arm elevation effect after exposure to simulated microgravity is not examined.

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掲載種別：研究論文（学術雑誌）  

In aged people, decreases in stroke volume and cardiac output during orthostatic challenge are less. It is suggested that the stiffness of blood vessels is greater in the elderly, blunting leg venous pooling and drop in central blood volume in an upright position. Leg venous hemodynamics plays an important role in human cardiovascular homeostasis against gravitational stress. This study aimed to clarify how aging influences the leg venous hemodynamics and its contribution to cardiovascular homeostasis during lower body negative pressure (LBNP) in humans.

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掲載種別：研究論文（学術雑誌）  

Six-degree head-down tilt (HDT) is well accepted as an effective weightlessness model in humans. However, some researchers utilized lower body positive pressure (LBPP) to simulate the cardiovascular and renal effects of a decreased gravitational stress. In order to determine whether LBPP was a suitable model for simulated weightlessness, we compared the differences between these two methods. Ten healthy males, aged 21-41 years, were subjected to graded LBPP at 10, 20 and 30 mmHg, as well as 6°HDT. Muscle sympathetic nerve activity (MSNA) was microneurographically recorded from the tibial nerve along with cardiovascular variables. We found that MSNA decreased by 27% to a similar extent both at low levels of LBPP (10 and 20 mmHg) and HDT. However, at a high level of LBPP (30 mmHg), MSNA tended to increase. Mean arterial pressure was elevated significantly by 11% (10 mmHg) at 30 mmHg LBPP, but remained unchanged at low levels of LBPP and HDT. Heart rate did not change during the entire LBPP and HDT procedures. Total peripheral resistance markedly increased by 36% at 30 mmHg LBPP, but decreased by 9% at HDT. Both stroke volume and cardiac output tended to decrease at 30 mmHg LBPP, but increased at HDT. These results suggest that although both LBPP and HDT induce fluid shifts from the lower body toward the thoracic compartment, autonomic responses are different, especially at LBPP greater than 20 mmHg. We note that high levels of LBPP (>20 mmHg) activate not only cardiopulmonary and arterial baroreflexes, but also intramuscular mechanoreflexes, while 6°HDT only activates cardiopulmonary baroreflexes. We conclude that LBPP is not a suitable model for simulated weightlessness in humans. Copyright (C) 2000 Elsevier Science B.V.

DOI： 10.1016/S0165-1838(00)00081-3

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掲載種別：研究論文（学術雑誌）  

The present study was performed to determine how sympathetic function is altered by simulated microgravity, dry immersion for 3 days, and to elucidate the mechanism of post-spaceflight orthostatic intolerance in humans. Six healthy men aged 21-36 years old participated in the study. Before and after the dry immersion, subjects performed head-up tilt (HUT) test to 30°and 60° (5 min each) with recordings of muscle sympathetic nerve activity (MSNA, by microneurography), electrocardiogram, and arterial blood pressure (Finapres). Resting MSNA was increased after dry immersion from 23.7±3.2 to 40.9±3.0 bursts/min (p<0.005) without significant changes in resting heart rate (HR). MSNA responsiveness to orthostasis showed no significant difference but HR response was significantly augmented after dry immersion (p<0.005). A significant diastolic blood pressure fall at 5th min of 60°HUT was observed in five orthostatic tolerant subjects despite enough MSNA discharge after dry immersion. A subject suffered from presyncope at 2 min after 60°HUT. He showed gradual blood pressure fall 10 s after 60°HUT with initially well-maintained MSNA response and then with a gradually attenuated MSNA, followed by a sudden MSNA withdrawal and abrupt blood pressure drop. In conclusion, dry immersion increased MSNA without changing MSNA response to orthostasis, and resting HR, while increasing the HR response to orthostasis. Analyses of MSNA and blood pressure changes in orthostatic tolerant subjects and a subject with presyncope suggested that not only insufficient vasoconstriction to sympathetic stimuli, but also a central mechanism to induce a sympathetic withdrawal might play a role in the development of orthostatic intolerance after microgravity exposure. Copyright (C) 2000 Elsevier Science B.V.

DOI： 10.1016/S0165-1838(99)00076-4

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掲載種別：研究論文（学術雑誌）  

We hypothesized that the relationship between resting levels of sympathetic vasoconstrictor nerve traffic and dilator substance nitric oxide (NO) release is altered after exposure to microgravity, resulting in abnormal peripheral resistance. To examine the hypothesis, we assessed muscle sympathetic nerve activity (MSNA) (microneurography), an indicator of NO release (plasma nitrite/nitrate concentrations) and leg vascular resistance (venous occlusion plethysmography) in 20 healthy male volunteers before and after 14 days of 6°head-down bed rest (HDBR), the ground-based analogue of microgravity. MSNA increased, while plasma nitrite/nitrate concentrations decreased after HDBR. A significant positive correlation observed between MSNA and plasma nitrite/nitrate concentrations before HDBR disappeared after HDBR. Leg vascular resistance increased after HDBR. In conclusion, an imbalance between sympathetic vasoconstrictor traffic and NO release might contribute to elevated peripheral vascular resistance following HDBR. (C) 2000 Elsevier Science Ireland Ltd.

DOI： 10.1016/S0304-3940(00)00804-1

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掲載種別：研究論文（学術雑誌）  

To examine the effect of 6°head-down bed rest (HDBR) on vasomotor sympathetic responses to isometric forearm exercise, 16 healthy male subjects aged 20-36 years performed voluntary isometric handgrip (HG) at 30% of maximal voluntary contraction until fatigue, followed by 2 min of post-handgrip muscle ischemia (PHGMI) with 250 mmHg of cuff inflation, before and after 14 days of HDBR. Time to fatigue and maximal voluntary HG force were not affected by HDBR. Pre-exercise baseline muscle sympathetic nerve activity (MSNA, measured by microneurography), heart rate (measured by electrocardiogram) and mean blood pressure (measured by Portapres) increased after HDBR. Increases in MSNA were similar during HG but significantly lower during PHGMI (P<0.01) after HDBR. Responses of heart rate and mean blood pressure during HG and PHGMI were not affected by HDBR. These results suggest that the magnitude of muscle metaboreflex during isometric forearm exercise might be attenuated after 14 days of simulated microgravity. Copyright (C) 2000 Published by Elsevier Science Ireland Ltd.

DOI： 10.1016/S0304-3940(99)00995-7

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掲載種別：研究論文（学術雑誌）  

To examine how long-lasting microgravity simulated by 6°head-down bed rest (HDBR) induces changes in the baroreflex control of muscle sympathetic nerve activity (MSNA) at rest and changes in responses of MSNA to orthostasis, six healthy male volunteers (range 26-42 yr) participated in Valsalva maneuver and head-up tilt (HUT) tests before and after 120 days of HDBR. MSNA was measured directly using a microneurographic technique. After long-term HDBR, resting supine MSNA and heart rate were augmented. The baroreflex slopes for MSNA during Valsalva maneuver (in supine position) and during 60°HUT test, determined by least-squares linear regression analysis, were significantly steeper after than before HDBR, whereas the baroreflex slopes for R-R interval were significantly flatter after HDBR. The increase in MSNA from supine to 60°HUT was not different between before and after HDBR, but mean blood pressure decreased in 60°HUT after HDBR. In conclusion, the baroreflex control of MSNA was augmented, whereas the same reflex control of R-R interval was attenuated after 120 days of HDBR.

DOI： 10.1152/ajpregu.2000.278.2.r445

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掲載種別：研究論文（学術雑誌）  

Background: Alterations in autonomic function are commonly seen during and after spaceflight, and its ground-based analog, 6°head-down bed rest (HDBR). They may include peripheral vascular regulation, but vasomotor sympathetic efferent nerve discharges to peripheral vasculatures have not been examined. The aim of our study was to examine changes in vasomotor sympathetic nerve activity during HDBR and under orthostasis after HDBR. Methods: We performed 6 d of HDBR on six male subjects, and measured muscle sympathetic nerve activity (MSNA) together with plasma norepinephrine concentrations in the supine position before HDBR and in 6°head-down position on the sixth day (HDBR6) of HDBR. We also measured MSNA in head-up tilt (HUT) test before and after HDBR. Results: On HDBR6, MSNA burst rate was the same (17 ± 4 bursts · min-1) as that in supine position before HDBR (15 ± 2 bursts, min-1), but plasma norepinephrine concentrations were decreased to 1.14 ± 0.10 pmol · ml-1 compared with the supine value before HDBR (1.56 ± 0.20 pmol · ml-1, p < 0.05). After HDBR, supine MSNA burst rate significantly increased by 55% to 24 ± 4 bursts · min-1. MSNA increment in response to HUT was similar between before (34 ± 3 bursts · min-1 · sin HUT-1) and after (40 ± 6 bursts · min-1 · sin HUT-1) HDBR. Conclusions: Our findings suggest that: a) the relationship between MSNA and plasma norepinephrine concentrations was altered on the sixth day during HDBR; b) the vasomotor sympathetic nerve activity was enhanced after HDBR; and c) the augmentation of vasomotor sympathetic outflow to muscles under orthostasis was preserved after HDBR.

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掲載種別：研究論文（学術雑誌）  

Astronauts usually work under much mental stress. However, it is unclear how and whether or not an exposure to microgravity affects physiological response to mental stress in humans. To examine effects of microgravity on vasomotor sympathetic and peripheral vasodilator responses to mental stress, we performed 10 min of mental arithmetic (MA) before and after 14 days of 6°head-down bed rest (HDBR), a ground-based simulation of spaceflight. Total muscle sympathetic nerve activity (MSNA, measured by microneurography) slightly increased during MA before HDBR, and this increase was augmented after HDBR. Calf blood flow (measured by venous occlusion plethysmography) increased and calf vascular resistance (calculated by dividing mean blood pressure by calf blood flow) decreased during MA before HDBR, but these responses were abolished after HDBR. Increases in heart rate and mean blood pressure during MA were not different between before and after HDBR. These findings suggest that HDBR augmented vasomotor sympathoexcitation but attenuated vasodilatation in the calf muscle in response to mental stress.

DOI： 10.1152/ajpregu.2000.279.2.r440

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掲載種別：研究論文（学術雑誌）  

To evaluate the fluid shift and leg venous compliance during orthostatic stress with advancing age, 12 aged and 5 young healthy males were subjected to graded lower body negative pressures (LBNP) of -5, -10, and -15 mmHg. Cardiovascular variables were monitored continuously, and leg venous compliance was determined by venous occlusion plethysmography. Neither heart rate nor mean arterial pressure changed significantly in any subject during LBNP. A progressive decrease in the thoracic fluid volume index and a gradual increase in the leg fluid volume index, indicating a fluid shift towards the lower body were observed significantly in the young group (p<0.05), while these changes were not significant in the aged group. A linear reduction in peripheral venous pressure could be seen during graded LBNP in all subjects, but the reduction rate was smaller in the aged group. Baseline leg venous compliance was reduced in the elderly (p<0.05). During LBNP, venous compliance decreased in all subjects, but the decrease was significantly smaller in the aged group (p<0.05). It is suggested that the smaller fluid shift and smaller decreased leg venous compliance in aged people during gravitational stress were mainly due to the vascular and ventricular stiffness induced by an age-related reduction in visco-elasticity of the peripheral venous and ventricular walls.

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掲載種別：研究論文（学術雑誌）  

The alterations in the sympathetic nervous system are commonly seen after spaceflight and its ground-based simulation model, 6 degrees head-down bed rest (HDBR). Several studies have examined the effect of HDBR for a few days or a weeks on the vasomotor sympathetic tone at rest. However, it remains unclear how a long-lasting (>50 days) HDBR affects resting vasomotor sympathetic nervous activity. Consequently, we measured muscle sympathetic nerve activity (MSNA) in six healthy male volunteers (range, 26-42 years) in a resting supine position before and after 60 and 120 days of HDBR. MSNA was measured directly from the tibial nerve using a microneurographic technique. Resting supine MSNA significantly increased after 60 (28.2 +/- 2.7 bursts/min) and 120 (29.4 +/- 4.2 bursts/min) days of HDBR compared with the pre-HDBR level (19.0 +/- 2.3 bursts/min). Heart rate was significantly higher after 60 (73 +/- 2 beats/min) and 120 (72 +/- 3 beats/min) days of HDBR than before (65 +/- 2 beats/min). In contrast, mean blood pressure remained unchanged during and after 120 days of HDBR. In conclusion, the resting vasomotor sympathetic tone increased after long-lasting simulated microgravity.

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掲載種別：研究論文（学術雑誌）  

We have investigated the changes in muscle sympathetic nerve activity (MSNA) from the tibial nerve during brief periods of microgravity (μG) for ~20 s produced by parabolic flight. MSNA was recorded microneurographically from 13 quietly seated human subjects with their knee joints extended in a jet aircraft simultaneously with the electrocardiogram, the blood pressure wave (measured with a Finapres), the respiration curve, and the thoracic fluid volume (measured by impedance plethysmography). During quiet and seated parabolic flight, MSNA was activated in hypergravity and was suppressed in μG phasically. At the entry to hypergravity at 2 G just before μG, the thoracic fluid volume was reduced by 3.2 ± 3%, and the arterial blood pressure was lowered transiently and then gradually elevated from 89.5 ± 1.7 to 100.2 ± 1.7 mmHg, which caused the enhancement of MSNA by 91.4 ± 14.2%. At the entry to μG, the thoracic fluid volume was increased by 3.4%, which lowered the mean blood pressure to 77.9 ± 2.3 mmHg and suppressed the MSNA by 17.2%. However, this suppression lasted only ~10 s, followed by an enhancement of MSNA that continued for several seconds. We conclude that MSNA is suppressed and then enhanced during μG produced by parabolic flight. These changes in MSNA are in response not only to intrathoracic fluid volume changes but also to arterial blood pressure changes, both of which are caused by body fluid shifts induced by parabolic flight, and these changes are quite phasic and transient.

DOI： 10.1152/ajpregu.1999.277.2.r419

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掲載種別：研究論文（学術雑誌）  

The mechanism of cardiovascular deconditioning, such as an orthostatic intolerance after space flight, has not been well clarified. Several studies to investigate that mechanism have focused mainly on hemodynamic changes including heart rate, arterial blood pressure, cardiac output, etc., but no studies have yielded a direct insight into changes in the sympathetic nervous system. Among ground-based experiments, parabolic flight is the only maneuver to expose human subjects to actual microgravity although it lasts for only a short duration of approx. 20 sec. Using microneurography, the present study aimed to analyze the involvement of the sympathetic nervous system in regulating the acute effects of fluid shift induced by parabolic flight during the transitional changes from 1 G to hypergravity, hypergravity to microgravity, and microgravity to hypergravity by direct measurement of sympathetic outflow to the muscles. Some parts of the study were published elsewhere. We also investigated how the sympathetic outflow to muscle is modified during microgravity with elimination of the breathing effect by comparing the cardiovascular parameters under controlled and uncontrolled respiration.

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掲載種別：研究論文（学術雑誌）  

Upon a return to the earth from spaceflight, astronauts often become presyncope during standing. This orthostatic intolerance is provoked by the exposure to the stimulation model of microgravitational environment in humans, 6 degrees head-down bed rest (HDBR). The mechanism for the orthostatic hypotension after microgravity remains unclear. It has been reported that a microgravity-induced loss of circulatory blood volume, a withdrawal of vagal tone, or a reduction of carotid-cardiac baroreflex function may relate to this phenomenon. A recent article has reported that astronauts who showed presyncopal events after spaceflight had subnormal increases in plasma norepinephrine under the standing tests, suggesting that a hypoadrenergic responsiveness to orthostatic stress may partly contribute to postflight orthostatic hypotension. However, it is unclear how and whether or not the sympathetic outflow to peripheral vessels and the release of norepinephrine from sympathetic nerve terminals were altered after microgravity. The vasomotor sympathetic outflow to the skeletal muscle can be directly recorded as muscle sympathetic nerve activity (MSNA) using a microneurographic technique. In addition, the rate of an increase in plasma norepinephrine per that in MSNA in response to applied orthostatic stress can partly indicate the norepinephrine release to sympathetic stimuli as a trial assessment. Therefore, we performed 60 degrees head-up tilt (HUT) tests before and after 14 days of HDBR, and examined the differences in the MSNA response and the indicated norepinephrine release during HUT tests between the subjects who did (defined as the fainters) and those who did not (defined as the nonfainters) become presyncopal in HUT tests after HDBR.

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掲載種別：研究論文（学術雑誌）  

Both lower body positive pressure (LBPP) and head-down tilt (HDT) can induce fluid shifts from the lower body to the thorax and result in a loading of cardiopulmonary baroreceptors. The aim of this study was to compare the effects of LBPP and HDT on cardiovascular responses in humans. To accomplish this, a graded LBPP test of 10, 20 and 30 mmHg, as well as a 6 degrees HDT was applied. It has been suggested that <20 mmHg LBPP and <30 degrees HDT load the cardiopulmonary baroreceptors by translocation of blood volume from the lower body to the thorax, while >20 mmHg LBPP activates the intramuscular pressure-sensitive receptors.

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掲載種別：研究論文（学術雑誌）  

During the isometric exercise, the autonomic nervous system has a major role in the regulation of arterial blood pressure, blood flow, and perfusion to the active skeletal muscle in humans. An increase in cardiac sympathetic nerve activity and a withdrawal of vagal tone cause elevations of heart rate, cardiac contractility and cardiac output. An increase in vasomotor sympathetic nerve activity causes a vascular constriction to redirect the oxygen transport to the contracting muscle. It has been reported that the autonomic and cardiovascular systems are commonly affected by the exposure to the real (i.e. spaceflight) and simulated microgravitational environment( i.e. 6 degrees head-down bed rest (HDBR)). The alteration in the autonomic system includes a reduced vagal tone, and an attenuated carotid-cardiac baroreflex function. It may also include an altered control of peripheral vessels, a reduced sympathetic vasoconstriction, an attenuated release of norepinephrine from sympathetic nerve terminal, an impaired myogenic contractility, an up- or down regulation of alpha-adrenergic receptors, and an attenuated multiple vasodilatation. Therefore, there seems to be a possibility that HDBR alters the sympathetic and cardiovascular responses to isometric exercise in humans, however, this possibility has not been examined efficiently. We compared the vasomotor sympathetic and cardiovascular responses to sustained handgrip (HG) until fatigue followed by post-exercise muscle ischemia (PEMI) after 14 days of HDBR, to those before HDBR, in 16 healthy males.

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掲載種別：研究論文（学術雑誌）  

Alterations in autonomic function are evident during spaceflight. These conditions are also simulated by ground-based experimental models of a microgravity environment such as 6 degrees head-down bed rest (BR). They include a reduction in baroreflex function, a decrease in vagal tone and a loss of circulatory blood volume during weightlessness. However, it is not clear whether vasomotor sympathetic outflow, which controls peripheral vascular tone neurally, and plasma norepinephrine concentration will change or not during weightlessness. The purpose of the present study is to examine changes in vasomotor sympathetic nerve activity during six days of 6 degrees head-down BR. Vasomotor sympathetic nervous activity was evaluated by the direct recording of muscle sympathetic nerve activity (MSNA) by a use of microneurographic technique. MSNA on the sixth day during BR was the same as that in a horizontally supine position before BR (before BR; 15.4 +/- 1.6 bursts/min, during BR; 16.7 +/- 3.5 bursts/min), though plasma norepinephrine concentrations during BR were reduced by 25% compared with those before BR (before BR; 263 +/- 33 pg/ml, during BR; 193 +/- 79 pg/ml, p < 0.05). This dissociation cannot be determined precisely, but it suggests the possibility of peripheral changes in terminal sympathetic nerve endings, etc.

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掲載種別：研究論文（学術雑誌）  

This study aimed to clarify how muscle sympathetic nerve activity (MSNA) in humans, which plays an important role in blood pressure control against gravity, is altered under microgravity (microG) conditions, and how the MSNA change is modified by breathing maneuvers. Ten subjects seated themselves in a jet aircraft with their knees extended. MSNA was recorded microneurographically from the left tibial nerve with simultaneous monitoring of ECG, blood pressure, respiration, and intrathoracic blood volume estimated by the impedance method during parabolic flight in a jet aircraft. In half of the parabolas, their respiration was controlled at 0.25 Hz by a metronome. Results: MSNA was enhanced under hypergravity just before microG entry, and immediately suppressed by microG induced by parabolic flight. The suppression was more marked with controlled than with uncontrolled respiration (51.6 +/- 7.2 vs 82.8 +/- 2.5%, mean +/- SE, 1G=100%). MSNA changes during microG correlated significantly to changes in blood pressure and intrathoracic blood volume. The blood pressure fall 10 to 15 sec after microG entry was less prominent with controlled than with uncontrolled respiration. We conclude that changes in arterial blood pressure and intrathoracic blood volume modulate MSNA during microG induced by parabolic flight, depending largely on breathing maneuvers.

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掲載種別：研究論文（学術雑誌）  

To elucidate the role of vasomotor sympathetic nerve activity response to lower-body positive pressure (LBPP), muscle sympathetic nerve activity (MSNA) along with blood pressure, electrocardiogram, transthoracic impedance and echocardiogram were recorded in ten healthy young men at 10, 20 and 30 mmHg LBPP in the supine position. We found that MSNA was suppressed (27%) at both 10 and 20 mmHg LBPP but tended to increase at 30 mmHg LBPP. Mean arterial pressure (11%) and total peripheral resistance (36%) increased despite a tendency toward decreased stroke volume and cardiac output at 30 mmHg LBPP. Heart rate remained unchanged. The left atrial dimension significantly increased during 10-30 mmHg LBPP, indicating an increase in cardiac filling. These results suggest that LBPP at levels less than 20 mmHg suppressed MSNA by the translocation of blood from the lower body to the thorax, thus stimulating the cardiopulmonary baroreceptors which in turn inhibited vasomotor sympathetic nerve activity. However, LBPP at 30 mmHg tended to enhance MSNA through the activation of intramuscular (pressure-sensitive) receptors which could counteract the inhibitory effect of cardiopulmonary baroreflexes on MSNA.

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掲載種別：研究論文（学術雑誌）  

The present paper aimed to review findings obtained by our researches to elucidate sympathetic nerve mechanisms of cardiovascular deconditioning in humans exposed to short and long term simulation of microgravity. Sympathetic nerve activity in humans has been so far investigated using indirect methods by analyzing the activities of effector organs, such as heart rate, blood flow, blood pressure, sweating etc. or by measuring the plasma nor-adrenaline level. Now we have a technique called microneurography which has enabled us to measure directly the sympathetic nerve activity form human peripheral nerves. The microneurography technique was used for the first time before, during and after the Space Shuttle "Neurolab" mission launched in April 1998 to elucidate how sympathetic nerve activity in astronauts is modified by exposure to microgravity in space. In this paper, we would like to present our recent findings concerning sympathetic nerve responses to short and long term microgravity simulated by different methods.

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掲載種別：研究論文（学術雑誌）  

We hypothesized that muscle sympathetic nerve activity (MSNA) and cardiovascular responses to the conventional head-up tilt (HUT) are different from those to head-up suspension (HUS) because of antigravity muscle activity. The MSNA from the tibial nerve, heart rate, blood pressure, stroke volume, cardiac output, and calf blood flow were measured in 13 healthy young subjects. Left atrial diameter was measured by two-dimensional echocardiography in another nine subjects. The resting MSNA and cardiovascular responses at a low level (20°) of orthostasis were similar during both modes. At higher levels (40 and 60°), the responses of MSNA, heart rate, stroke volume, and cardiac output were significantly stronger and there was a smaller reduction in calf blood flow during HUT than during HUS (P < 0.05). Left atrial diameter was decreased significantly from the resting values during HUT and HUS without any significant difference between the modes of orthostasis. The results provide evidence that the engagement of antigravity muscles during HUT may have additive effects on sympathetic vasoconstrictor and cardiovascular responses to orthostatic stress.

DOI： 10.1152/jappl.1998.84.5.1513

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掲載種別：研究論文（学術雑誌）  

To evaluate the response of vasomotor sympathetic nerve activity to lower body positive pressure (LBPP), muscle sympathetic nerve activity (MSNA) was microneurographically recorded from the tibial nerve in 10 healthy young men, along with hemodynamic variables and echocardiogram, during exposure to incremental LBPP at 10, 20, and 30 mmHg in the supine position. MSNA was suppressed to a similar extent (27%) at 10- and 20-mmHg LBPP. However, at 30- mmHg LBPP, MSNA tended to increase but was still nearly at the control value. Mean arterial pressure was elevated (11%), total peripheral resistance markedly increased (36%), and stroke volume and cardiac output tended to decrease at 30-mmHg LBPP. Heart rate remained unchanged throughout the procedures. Left atrial dimension significantly increased during 10- and 30- mmHg LBPP, indicating an increased cardiac filling. These results suggest that the inhibitory effect of the cardiopulmonary baroreflex on MSNA at 10- and 20-mmHg LBPP could be counteracted by the sympathoexcitatory effect of the intramuscular pressure-sensitive mechanoreflex at 30-mmHg LBPP. However, the increment of total peripheral resistance at 30-mmHg LBPP may not depend exclusively on this small enhancement of MSNA.

DOI： 10.1152/ajpheart.1998.275.4.h1254

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記述言語：日本語  

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記述言語：英語   出版者・発行元：社団法人日本循環器学会  

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記述言語：英語   出版者・発行元：社団法人日本循環器学会  

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記述言語：英語   出版者・発行元：社団法人日本循環器学会  

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記述言語：英語   出版者・発行元：社団法人日本循環器学会  

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記述言語：英語   出版者・発行元：社団法人日本循環器学会  

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記述言語：英語   出版者・発行元：社団法人日本循環器学会  

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記述言語：英語   出版者・発行元：社団法人日本循環器学会  

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記述言語：日本語  

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記述言語：日本語   出版者・発行元：日本体力医学会  

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